Leukotriene-b4 derivatives, process for their production and their use as pharmaceutical agents

ABSTRACT

##STR1## Compounds of formula (I) in which the residues have the following meanings: a is (II) or (III); R 1  is CH 2  OH, CH 3 , CF 3 , COOR 5  with R 5  or, A is a trans, trans--CH═CH--CH═CH--or tetramethylene group; B is an alkylene group with up to 10 C atoms; D is a direct bond, oxygen, sulphur, a --C.tbd.C--group or a --CH═CR 7  --group, or (IV); B and D together are a direct bond; R 2  and R 3  are the same or different and denote hydrogen or an organic acid residue with 1 to 15 C atoms, R 1  and R 2  together are a carbonyl group; R 4  is a hydrogen atom or C 1-10  alkyl, and if R 5  denotes a hydrogen atom, their salts with physiologically acceptable bases and their cyclodextrin clathrates.

The invention relates to new leukotriene-B₄ derivatives, the process fortheir production as well as their use as pharmaceutical agents.

Leukotriene B₄ (LTB₄) was discovered in 1979 by B. Samuelsson et al. asa metabolite of arachidonic acid. In the biosynthesis, leukotriene A₄ isformed by the enzyme 5-lipoxygenase first as a central intermediateproduct, which then is converted by a specific hydrolase to the LTB₄.

KEY

Arachidonsaeure=arachidonic acid

Lipoxygenase=lipoxygenase

Dehydrase=dehydrase

Leukotrien A₄ (LTA₄)=leukotriene A₄ (LTA₄)

Hydrolase=hydrolase

Glutathion-S-transferase=glutathione-S-transferase

Leukotrien B₄ (LTB₄)=leukotriene B₄ (LTB₄)

Leukotrien C₄ (LTC₄)=leukotriene C₄ (LTC₄) ##STR2##

The nomenclature of the leukotrienes can be gathers from the followingworks:

a) B. Samuelsson et al., Prostaglandins 19, 645 (1980); 17, 785 (1979).

b. C. N. Serhan et al., Prostaglandins 34, 201 (1987).

The physiological and especially the pathophysiological importance ofleukotriene B₄ is summarized in several more recent works: 1: TheLeukotriene, Chemistry and Biology eds. L. W. Chakrin, D. M. Bailey,Academic Press 1984. b) J. W. Gillard et al., Drugs of the Future 12,453 (1987). c) B. Samuelsson et al., Science 237, 1171 (1987). d) C. W.Parker, Drug Development Research 10, 277 (1987). It follows from theabove that LTB₄ is an important inflammation mediator for inflammatorydiseases, in which leukocytes invade the affected tissue.

It is known that LTB₄ causes the adhesion of leukocytes on the bloodvessel wall. LTB₄ is chemotactically effective, i.e., it triggers adirected migration of leukocytes in the direction of a gradient ofincreasing concentration. Further, because of its chemotactic activity,it indirectly changes the vascular permeability, and a synergism withprostaglandin E₂ is observed. LTB₄ obviously plays a decisive role ininflammatory, allergic and immunological processes.

Leukotrienes and especially LTB₄ are involved in skin diseases, whichaccompany inflammatory processes (increased vessel permeability andformation of edemas, cell infiltration), increased proliferation of skincells and itching, such as, for example, in eczemas, erythemas,psoriasis, pruritus and acne. Pathologically increased leukotrieneconcentrations are involved either causally in the development of manydermatitides or there is a connection between the persistence of thedermatitides and the leukotrienes. Clearly increased leukotrieneconcentrations were measured, for example, in the skin of patients withpsoriasis or atopic dermatitis.

Further, leukotrienes and LTB₄ are involved especially in arthritis,chronic lung diseases (e.g., asthma), rhinitis and inflammatoryintestinal diseases.

Antagonists against LTB₄ receptors or inhibitors of those enzymes, whichare involved in the synthesis of the LTB₄, should be effective asspecific medications, especially against diseases which accompanyinflammations and allergic reactions.

Besides the therapeutic possibilities, which can be derived from anantagonizing of LTB₄ with LTB₄ analogs, the usefulness and potential useof leukotriene-B₄ agonists for the treatment of fungus diseases of theskin was also able to be shown recently (H. Kayama, Prostaglandins 34,797 (1988)).

It has now been found that the incorporation of the chemically andmetabolically labile cis-delta⁶,7 double bond of LTB₄ in acis-1,2-substituted cyclohexyl ring or a trans-1,2-substitutedcyclohexyl ring results in a stabilization, and especially by furtherderivatizing of the functional groups, LTB₄ derivatives are obtainedwhich greatly antagonize the action of the natural LTB₄. I.e., theinvention comprises LTB₄ analogs, which can act as antagonists.

The invention relates to compounds of formula I, ##STR3## in which theradicals have the following meanings: ##STR4##

R¹ is CH₂ OH, CH₃, CF₃, COOR⁵ with R⁵ meaning a hydrogen atom, an alkylradical with 1-10 C atoms, a cycloalkyl radical with 3-10 C atoms, anaryl radical with 6-10 C atoms optionally substituted by 1-3 chlorine,bromine, phenyl, C₁₋₄ alkyl, C₁₋₄ alkoxy, chloromethyl, fluoromethyl,trifluoromethyl, carboxy or hydroxy, a --CH₂ --CO--aryl radical with6-10 C atoms for an aryl or a 5-6-member aromatic heterocyclic radicalwith at least 1 heteroatom, or

R¹ is CONHR⁶ with R⁶ meaning an alkanoyl radical or an alkanesulfonylradical with 1-10 C atoms or radical R⁵ ;

A is a trans, trans--CH═CH--CH═CH-- group or a tetramethylene group;

B is a straight-chain or branched-chain, saturated or unsaturatedalkylene group with up to 10 C atoms which can optionally be substitutedby fluorine, or the group ##STR5## with n=1-3;

D is a direct bond, oxygen, sulfur, a --C.tbd.C group or a --CH═CR⁷group with R⁷ as hydrogen, C₁₋₅ alkyl, chlorine, bromine or ##STR6##

B and D together are a direct bond,

R² and R³ are the same or different and mean hydrogen or an organic acidradical with 1-15 C atoms;

R¹ and R² together are a carbonyl group;

R⁴ is a hydrogen atom, C₁₋₁₀ alkyl, which can optionally be substitutedby chlorine or bromine, cycloalkyl with 3-10 C atoms, an aryl radicalwith 6-10 C atoms optionally substituted by 1-3 chlorine, bromine,phenyl, C₁₋₄ alkyl, C₁₋₄ alkoxy, chloromethyl, fluoromethyl,trifluoromethyl, carboxy or hydroxy or a 5-6-member aromaticheterocyclic radical with at least 1 heteroatom, and if

R⁵ means a hydrogen atom, their salts with physiologically compatiblebases and their cyclodextrin clathrates.

Groups OR² and OR³ can be in alpha-position or beta-position. Formula Icomprises both racemates and the possible pure diastereomers andenantiomers.

As alkyl groups R⁵, straight-chain or branched-chain alkyl groups with1-10 C atoms, such as, for example, methyl, ethyl, propyl, butyl,isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, decyl, aresuitable. The alkyl groups R⁵ can optionally be substituted one or moretimes by halogen atoms, alkoxy groups, optionally substituted aryl oraroyl groups with 6-10 C atoms (substitution s. under aryl R⁵),dialkylamino and trialkylammonium with 1-C atoms in the alkyl portion,in which case the simple substitution is to be preferred. Assubstituents, for example, there can be mentioned fluorine, chlorine orbromine, phenyl, dimethylamine, diethylamine, methoxy, ethoxy. Aspreferred alkyl groups R⁵, those with 1-4 C atoms can be mentioned.

As aryl groups R⁵, both substituted and unsubstituted aryl groups with6-10 C atoms are suitable, such as, for example, phenyl, 1-naphthyl and2-naphthyl, which can be respectively substituted by 1-3 halogen atoms(F, Cl, Br), a phenyl group, 1-3 alkyl groups with 1-4 C atoms each, achloromethyl group, fluoromethyl group, trifluoromethyl group, carboxylgroup, hydroxy group or alkoxy group with 1-4 C atoms. Preferredsubstituents in 3- and 4-position in the phenyl ring are, for example,fluorine, chlorine, alkoxy or trifluoromethyl, but in 4-positionhydroxy.

The cycloalkyl group R⁵ can contain in the ring 3-10 carbon atoms,preferably 5 and 6 carbon atoms. The rings can be substituted by alkylgroups with 1-4 carbon atoms. For example, there can be mentionedcyclopentylhexyl, cyclohexyl, methylcyclohexyl.

As heterocyclic groups R⁵, 5- and 6-member aromatic heterocycles, whichcontain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur,are suitable. For example, there can be mentioned 2-furyl, 2-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl,pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, 2-tetrazolyl, i.a.

As acid radical R⁶. physiologically compatible acid radicals aresuitable. Preferred acids are organic carboxylic acids and sulfonicacids with 1-15 carbon atoms, which belong to the aliphatic,cycloaliphatic, aromatic, aromatic-aliphatic and heterocyclic series.These acids can be saturated, unsaturated and/or polybasic and/orsubstituted in the usual way. As examples for the substituents, therecan be mentioned C₁₋₄ alkyl groups, hydroxy groups, C₁₋₄ alkoxy group,oxo groups or amino groups or halogen atoms (F, Cl, Br). For example,the following carboxylic acids can be mentioned: formic acid, aceticacid, propionic acid, butyric acid, isobutyric acid, valeric acid,isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonicacid, capric acid, undecylic acid, lauric acid, tridecylic acid,myristic acid, pentadecylic acid, trimethylacetic acid, diethylaceticacid, tert-butylacetic acid, cyclopropylacetic acid, cyclopentylaceticacid, cyclohexylacetic acid, cyclopropanecarboxylic acid,cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid,methoxyacetic acid, ethoxyacetic acid, mono-, di- and trichloroaceticacid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid,morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoicacid, benzoic acids substituted with halogen (F, Cl, Br) ortrifluoromethyl groups, hydroxy groups, C₁₋₄ alkoxy groups or carboxygroups, nicotinic acid, isonicotinic acid, 2-furancarboxylic acid,cyclopentylpropionic acid. As especially preferred acyl radicals andalkanesulfonyl radicals, those with up to 10 carbon atoms are suitable.As sulfonic acids, for example, methanesulfonic acid, ethanesulfonicacid, isopropanesulfonic acid, beta-chloroethanesulfonic acid,butanesulfonic acid, cyclopentanesulfonic acid, cyclohexanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid,p-chlorobenzenesulfonic acid, N,N-dimethylaminosulfonic acid,N,N-diethylaminosulfonic acid, N,N-bis(beta-chloroethyl)aminosulfonicacid, N,N-diiosbutylaminosulfonic acid, N,N-dibutylaminosulfonic acid,pyrrolidino-, piperidino-, piperazino-, N-methylpiperazino- andmorpholino-sulfonic acid are suitable.

As alkyl groups R⁴, straight-chain and branched-chain, saturated andunsaturated alkyl radicals, preferably saturated, with 1-14, especially1-10 C atoms are suitable, which optionally can be substituted byoptionally substituted phenyl (substitution see under aryl R⁵). Forexample, there can be mentioned the methyl, ethyl, propyl, butyl,isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl,propenyl, pentenyl, benzyl, m- and p-chlorobenzyl groups. If alkylgroups R₄ are halogen-substituted, fluorine, chlorine and bromine aresuitable as halogens.

As an example for halogen-substituted alkyl groups R⁴, alkyls withterminal trifluoromethyl groups are suitable.

The cycloalkyl group R⁴ can contain in the ring 3-10 carbon atoms,preferably 3-6 carbon atoms. The rings can be substituted by alkylgroups with 1-4 carbon atoms. For example, there can be mentionedcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl.

As substituted or unsubstituted aryl groups R⁴ for example, phenyl,1-naphthyl and 2-naphthyl, which can each be substituted by 1-3 halogenatoms, a phenyl group, 1-3 alkyl groups each with 1-4 C atoms, achloromethyl group, fluoromethyl group, trifluoromethyl group, carboxylgroup, C₁ -C₄ alkoxy group or hydroxy group, are suitable. Thesubstitution in 3- and 4-position in the phenyl ring is preferred, forexample, by fluorine, chlorine, alkoxy or trifluoromethyl or in4-position by hydroxy.

As heterocyclic aromatic groups R⁴, 5- and 6-member heterocycles thatcontain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur,are suitable. For example, there can be mentioned 2-furyl, 2-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl,pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, i.a.

As alkylene group B, straight-chain or branched-chain, saturated orunsaturated alkylene radicals, preferably saturated with 1-10 C atoms,especially with 1-5 C atoms, which optionally can be substituted byfluorine atoms, are suitable. For example, there can be mentioned:methylene, fluoromethylene, difluoromethylene, ethylene, 1,2-propylene,ethylethylene, trimethylene, tetramethylene, pentamethylene,1,2-difluoroethylene, 1-fluoroethylene, 1-methyltetramethylene, 1-methyltrimethylene, 1-methylene-ethylene, 1-methylene-tetramethylene.

Alkylene group B can further constitute group ##STR7## in which casen=1-3, preferably 2-3.

As acid radicals R² and R³, physiologically compatible acid radicals aresuitable. Preferred acids are organic carboxylic acids and sulfonicacids with 1-15 carbon atoms, which belong to the aliphatic,cycloaliphatic, aromatic, aromatic-aliphatic or heterocyclic series.These acids can be saturated, unsaturated and/or polybasic and/orsubstituted in the usual way. As examples for the substituents, therecan be mentioned C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, oxo or amino groupsor halogen atoms (F, Cl, Br).

For example, the following carboxylic acids can e mentioned: formicacid, acetic acid, propionic acid, butyric acid, isobutyric acid,valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylicacid, pelargonic acid, capric acid, undecylic acid, lauric acid,tridecylic acid, myristic acid, pentadecylic acid, trimethylacetic acid,diethylacetic acid, tert-butylacetic acid, cyclopentylacetic acid,cyclohexylacetic acid, cyclohexanecarboxylic acid, phenylacetic acid,phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di-and tri-chloroacetic acid, aminoacetic acid, diethylaminoacetic acid,piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinicacid, adipic acid, benzoic acid, benzoic acids substituted with halogen(F, Cl, Br), trifluoromethyl, hydroxy, C₁₋₄ alkoxy or carboxy groups,nicotinic acid, isonicotinic acid, 2-furancarboxylic acid,cyclopentylpropionic acid. As especially preferred acid radicals R² andR³, acyl radicals with up to 10 carbon atoms are suitable.

R² as a C₁₋₅ alkyl manes straight-chain or branched-chain alkyl radicalssuch as those which have already been mentioned for R⁴ and R⁵. Preferredalkyl radicals R⁷ are methyl, ethyl, propyl and isopropyl.

Inorganic and organic bases are suitable for salt formation, as they areknown to one skilled in the art for forming physiologically compatiblesalts. For example, there can be mentioned alkali hydroxides, such assodium hydroxide and potassium hydroxide, alkaline earth hydroxides,such as calcium hydroxide, ammonia, amines, such as ethanolamine,diethanolamine, triethanolamine, n-methylglucamine, morpholine,tris(hydroxymethyl)methylamine, etc.

Preferred compounds of this invention are compounds of formula I, inwhich the radicals have the following meaning: ##STR8##

R¹ is CH₂ OH, COOR⁵ with R⁵ meaning a hydrogen atom, an alkyl radicalwith 1-10 C atoms, a cycloalkyl radical with 5-6 C atoms, a phenylradical optionally substituted by 1-2 chlorine, bromine, phenyl, C₁₋₄alkyl, C₁₋₄ alkoxy, chloromethyl, fluoromethyl, trifluoromethyl, carboxyor hydroxy, or

R¹ is CONHR⁶ with R⁶ meaning an alkanoyl radical or an alkanesulfonylradical with 1-10 C atoms or radical R⁵ ;

A is a trans, trans--CH═CH--CH═CH-- group or a tetramethylene group;

B is a straight-chain or branched chain, saturated or unsaturatedalkylene group with up to 10 C atoms which can optionally be substitutedby fluorine, or the group ##STR9## with n=1-3;

D is a direct bond, oxygen, sulfur, a --CH.tbd.C group or a --CH═CR⁷group with R⁷ as hydrogen, C₁₋₅ alkyl, chlorine, bromine or ##STR10##

B and D together are a direct bond,

R² and R³ are the same or different and mean hydrogen or an organic acidradical with 1-15 C atoms;

R¹ and R² together are a carbonyl group;

R⁴ is a hydrogen atom, C₁₋₁₀ alkyl, cycloalkyl with 5-6 C atoms, aphenyl radical optionally substituted by 1-2 chlorine, bromine, phenyl,C₁₋₄ alkyl, C₁₋₄ alkoxy, chloromethyl, fluoromethyl, trifluoromethyl,carboxy or hydroxy, and if

R⁵ means a hydrogen atom, their salts with physiologically compatiblebases and their cyclodextrin clathrates.

Especially preferred compounds of this invention are compounds offormula I, in which the radicals have the following meaning: ##STR11##

R¹ is CH₂ OH, COOR⁵ with R⁵ meaning a hydrogen atom, an alkyl radicalwith 1-4 C atoms;

A is a trans, trans--CH═CH--CH═CH-- group or a tetramethylene group;

B is a straight-chain or branched-chain alkylene group with up to 5 Catoms;

D is a direct bond or a --C.tbd.C group or a --CH═CR⁷ group with R⁷ ashydrogen or C₁₋₅ alkyl or ##STR12##

B and D together are a direct bond,

R² and R³ are the same or different and mean hydrogen or an organic acidradical with 1-6 C atoms;

R¹ and R² together are a carbonyl group;

R⁴ is a hydrogen atom or a C₁₋₁₀ alkyl, and if R⁵ means a hydrogen atom,their salts with physiologically compatible bases and their cyclodextrinclathrates.

The invention further relates to a process for the production of thecompounds of formula I according to the invention, which ischaracterized in that an aldehyde of formula II, ##STR13## in which A,B, D, and R⁴ have the above-indicated meaning, and R^(3') means silylprotecting groups, as then are mentioned for R⁸, optionally afterprotection of free hydroxy groups with a magnesium organic compound offormula III,

    X--Mg--CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --O--R.sup.8 (III),

in which X means chlorine, bromine or iodine and R⁸ means an easilycleavable ether radical, is reacted and then optionally separated intoany sequence of isomers, protected hydroxy groups are released and/or afree hydroxy group is esterified and/or the 1-hydroxy group is oxidizedto carboxylic acid and/or double bonds are hydrogenated and/or anesterified carboxyl group (R¹ =COOR⁵) is saponified and/or reducedand/or a carboxyl group R⁵ =H) is esterified and/or a free carboxy group(R⁵ ≦H) is converted to an amide (R¹ =CONHR⁶) or a carboxyl group with aphysiologically compatible base is converted to a salt.

As ether radicals R⁸ and R^(3') in the compound of formulas II and III,the radicals familiar to one skilled in the art are suitable. Easilycleavable ether radicals, such as, for example,dimethyl-tert-butylsilyl, trimethylsilylethyl, tribenzylsilylethyl,diphenyl-tert-butylsilylethyl, tetrahydropyranylethyl,tetrahydrofuranylethyl and alpha-ethoxyethyl are preferred, to mentiononly a few.

The reaction of the compound of formula II with an organometalliccompound of formula III takes place in a way known in the art in aninert solvent or solvent mixture, such as, for example, diethyl ether,tetrahydrofuran, dioxane, toluene, dimethoxyethane, preferably diethylether or tetrahydrofuran. The reaction is performed at temperaturesbetween -100° C. and 60° C., preferably at -78° C. to 0° C.

The production of the compound of formula III needed for this reactiontakes place by the reaction of the corresponding hydroxyhalide byetherification with dihydropyran and p-toluenesulfonic acid and thenreaction with magnesium.

The reduction to the compounds of formula I with R¹ meaning a CH₂ --OHgroup is performed with a reducing agent suitable for the reduction ofesters or carboxylic acids, such as, for example, lithium aluminumhydride, diisobutyl aluminum hydride, etc. As solvents, diethyl ether,tetrahydrofuran, dimethoxyethane, toluene, etc. are suitable. Thereduction is performed at temperatures of -30° C. up to the boilingtemperature of the solvent used, preferably 0° C. to 30° C.

The esterification of the alcohols of formula I (R² =H and/or R³ =H)takes place in a way known in the art. For example, the esterificationtakes place in than an acid derivative, preferably an acid halide or anacid anhydride, is reacted in the presence of a base such as, forexample, NaH, pyridine, triethylamine, tributylamine or4-dimethylaminopyridine with an alcohol of formula I. The reaction canbe performed without a solvent or in an inert solvent, preferablyacetone, acetonitrile, dimethylacetamide, DMSO at temperatures above orbelow room temperature, for example between -80° C. to 100° C.,preferably at room temperature.

The oxidation of the 1-hydroxy group is performed according to methodsknown to one skilled in the art. As oxidizing agents, for example,pyridinium dichromate (Tetrahedron Letters, 1979, 399), Jones reagent(J. Chem. Soc., 1953, 2555) or platinum/oxygen (Adv. In carbohydrateChem. 17, 169 (1962)) or Collins oxidation and then Jones oxidation canbe used. The oxidation with pyridinium dichromate is performed attemperatures of 0° C. to 100° C., preferably 20° C. to 40° C. in asolvent inert toward the oxidizing agent, for example,dimethylformamide.

The oxidation with Jones reagent is performed at temperatures of -40° C.to +40° C., preferably 0° C. to 30° C. in acetone as a solvent.

The oxidation with platinum/oxygen is performed at temperatures of 0° C.to 60° C. preferably 20° C. to 40° C. in a solvent inert toward theoxidizing agent such as, e.g. ethyl acetate.

The saponification of the esters of formula I is performed according tomethods known to one skilled in the art, such as, for example, withbasic catalysts. The compounds of formula I can be separated by theusual separation methods into the optical isomers.

The release of the functionally modified hydroxy groups takes placeaccording to known methods. For example, the cleavage of hydroxyprotecting groups, such as, for example, the tetrahydropyranyl radical,is performed in an aqueous solution of an organic acid, such as, e.g.,oxalic acid, acetic acid, propionic acid, i.a., or in an aqueoussolution of an inorganic acid such as e.g., hydrochloric acid. Toimprove the solubility, a suitably water-miscible inert organic solventis added. Suitable organic solvent are, e.g., alcohols, such as methanoland ethanol, and ethers, such as dimethoxyethane, dioxane andtetrahydrofuran. Tetrahydrofuran is preferably used. The cleavage isperformed preferably at temperatures between 20° C. and 80° c. Thecleavage of the silyl ether protecting groups takes place, for example,with tetrabutylammonium fluoride or with potassium fluoride in thepresence of a crown ether. As a solvent, for example, tetrahydrofuran,diethyl ether, dioxane, methylene chloride, etc., are suitable. Thecleavage is performed preferably at temperatures between 0° C. and 80°C.

The saponification of the acyl groups takes place, for example, withalkali or alkaline-earth carbonates or hydroxides in an alcohol or inthe aqueous solution of an alcohol. As an alcohol, aliphatic alcoholsare suitable, such as e.g., methanol, ethanol, butanol, etc., preferablymethanol. As alkali carbonates and hydroxides, potassium salts andsodium salts can be mentioned. The potassium salts are preferred.

As alkaline-earth carbonates and hydroxides, for example, calciumcarbonate, calcium hydroxide and barium carbonate are suitable. Thereaction takes place at -10° C. to +70° c., preferably at +25° C.

The introduction of the ester group ##STR14## for R¹, in which R⁵represents an alkyl group with 1-10 C atoms, takes place according tomethods known to one skilled in the art. The 1-carboxyl compounds arereacted, for example, with diazohydrocarbons in a way known in the art.The esterification with diazohydrocarbons takes place, e.g., in that asolution of the diazohydrocarbon in an inert solvent, preferably indiethyl ether, is mixed with the 1-carboxy compound in the same or inanother inert solvent, such as, e.g., methylene chloride. Aftercompletion of the reaction in 1 to 30 minutes, the solvent is removedand the ester is purified in the usual way. Diazoalkanes are eitherknown or can be produced according to known methods [Org. ReactionsVol., 8, pages 389-394 (1954)].

The introduction of the ester group ##STR15## for R¹, in which R²represents a substituted or unsubstituted aryl group, takes placeaccording to methods known to one skilled in the art. For example, the1-carboxy compounds with the corresponding arylhydroxy compounds in aninert solvent are reacted with dicyclohexylcarbodiimide in the presenceof a suitable base, for example, pyridine, DMAP, triethylamine. As asolvent, methylene chloride, ethylene chloride, chloroform, ethylacetate, tetrahydrofuran, preferably chloroform, are suitable. Thereaction is performed at temperatures between -30° C. and +50° C.,preferably at 10° C.

If C═C double bonds contained in the primary product are to be reduced,the hydrogenation takes place according to methods known in the art.

The hydrogenation of the delta⁸,10 -diene system is performed, in a wayknown in the art, at low temperatures, preferably at about -20° C. to+30° C. in a hydrogen atmosphere in the presence of a noble metalcatalyst. As a catalyst, for example, 10% palladium on carbon issuitable.

The leukotriene-B₄ derivatives of formula I with R¹ meaning a COOH groupcan be converted to a salt with suitable amounts of the correspondinginorganic bases with neutralization. For example, during dissolving ofthe corresponding acids in water, which contains the stoichiometricamount of the base, the solid inorganic salt is obtained after theevaporating off of the water or after the addition of a water-misciblesolvent, e.g., alcohol or acetone.

For the production of an amine salt, the LTB₄ acid, e.g., is dissolvedin a suitable solvent, for example, ethanol, acetone, diethyl ether,acetonitrile or benzene, and at least the stoichiometric amount of theamine is added to this solution. In this way, the salt usuallyaccumulates in solid form or is isolated after evaporation of thesolvent in the usual way.

The introduction of the amide group ##STR16## for R¹ takes placeaccording to methods known to one skilled in the art. The carboxylicacids of formula I (R⁵ =H) are first converted in the presence of atertiary amine, such as, for example, triethylamine, with chloroformicacid isobutyl ester to the mixed anhydride. The reaction of the mixedanhydride with the alkali salt of the corresponding amide or withammonia (R⁶ =H) takes place in an inert solvent or solvent mixture, suchas, for example, tetrahydrofuran, dimethoxyethane, dimethylformamide,hexamethylphosphoric acid triamide, at temperatures between -30° C. and+60° C., preferably at 0° C. to 30° C.

Another possibility for the introduction of the amide group ##STR17##for R¹ is in the reaction of a 1-carboxylic acid of formula I (R⁵ =H),in which free hydroxy groups optionally are protected intermediatelywith compounds of formula IV,

    O═C═N--R.sup.6                                     (IV),

in which R⁶ has the above indicated meaning.

The reaction of the compound of formula I (R⁵ ≦H) with an isocyanate offormula IV optionally takes place with the addition of a tertiary amine,such as, e.g., triethylamine or pyridine. The reaction can be performedwithout a solvent or in an inert solvent, preferably acetonitrile,tetrahydrofuran, acetone, dimethylacetamide, methylene chloride, diethylether, toluene, at temperatures between -80° C. to 100° C., preferablyat 0° C. to 30° c.

If the initial product contains OH groups in the leukotriene-B₄ radical,these OH groups are also reacted. Finally, if end products are desiredwhich contain free hydroxyl groups, a start is suitably made from theinitial products, in which these are intermediately protected bypreferably easily cleavable ether or acyl radicals.

The separation of enantiomers and/or diastereomers takes place accordingto methods known to one skilled in the art., e.g., by chromatographicmethods, for example, high-pressure liquid chromatography on opticallyactive supply materials.

The compounds of formula II used as initial material can be produced,for example, by 2-hydroxymethylbenzyl alcohol being converted to themonosilyl ether of formula V in a way known in the art. ##STR18##

By oxidation, e.g., with Collins reagent or by the Swern process, thealdehyde of formula VI is obtained, ##STR19## which is converted in aWittig-Horner olefinization with the phosphonate of formula VII and abase and optionally subsequent hydrogenation to the ester of formulaVIII, in which A ##STR20## has the above-indicated meaning. As bases,for example, potassium-tert-butylate, diazabicyclononane or sodiumhydride are suitable. The reduction of the ester group, for example,with DIBAH and then oxidation of the primary alcohol obtained, e.g.,with manganese dioxide or Collins reagent, results in the aldehyde offormula IX ##STR21##

The organometallic reaction of the aldehyde of formula IX with aGrignard reagent of formula X, in which B, D

    X--Mg--B--D--R.sup.4                                       (X)

and R⁴ exhibit the above-indicated meanings and X means chlorine,bromine or iodine, results after protection of the hydroxy group andoptionally diastereomer separation (for example by acylation) in thecompounds of formula XI ##STR22##

The production of the compound of formula X needed for theorganometallic reaction takes place by the reaction of the correspondingterminal halide with magnesium. By reaction of silyl ether XI withtetrabutylammonium fluoride, the alcohol of formula XII is obtained.##STR23##

The oxidation of the primary alcohol group in XII, e.g., with Collinsreagent or pyridinium dichromate, results in the aldehyde of formula II.

In the compounds of formula XI, in which B means a CH₂ group and D meansa --C.tbd.C-- group or a CH═CR⁷ group, a propargyl halide can beattained, for example by an organometallic reaction, with the aldehydeof formula IX and subsequent alkylation with a corresponding alkylhalide and optionally subsequent Lindlar hydrogenation.

The compounds of formula I act in an anti-inflammatory and anti-allergicmanner. In addition, they have antimycotic properties. Consequently, thenew leukotriene-B₄ derivatives of formula I represent valuablepharmaceutical active ingredients. The compounds of formula I areespecially suitable for topical application, since they exhibit adissociation between desirable topical effectiveness and undesirablesystemic side effects.

The new leukotriene-B₄ derivatives of formula 1 are suitable incombination with the auxiliary agents and vehicles usual in galenicpharmaceutics for topical treatment of contact dermatitis, eczemas ofthe most varied types, neurodermatoses, erythrodermia, burns, tinea,pruritus vulvae, pruritus ani, rosacea, lupus erythematosus cutaneus,psoriasis, lichen ruber planus and verrucosis and similar skin diseases.

The production of pharmaceutical agent specialties takes place in theusual way, by the active materials with suitable additions beingconverted into the desired form of application such as, for example:solutions, lotions, ointments, creams or plasters.

In the pharmaceutical agents thus formulated, the active ingredientconcentration is dependent on the form of application. In lotions andointments, an active ingredient concentration of 0.0001% to 1% ispreferably used.

Further, the new compounds optionally in combination with the usualvehicles and auxiliary agents are also very suitable for the productionof inhalants, which can be used for the treatment of allergic diseasesof the respiratory system such as, for example, bronchial asthma orrhinitis.

Further, the new leukotriene-B₄ derivatives also are suitable in theform of capsules, tablets or coated tablets, which preferably contain0.1 to 100 mg of active ingredient or are applied orally in the form ofsuspensions, which preferably contain 1-200 mg of active ingredient perdosage unit, and are also applied rectally to treat allergic diseases ofthe intestinal tract, such as colitis ulcerosa and colitisgranulomatosa.

The new leukotriene-B₄ derivatives can also be used combined with, e.g.,lipoxygenase inhibitors, cyclooxygenase inhibitors, prostacyclinagonists, thromboxane antagonists, leukotriene-D₄ antagonists,leukotriene-E₄ antagonists, leukotriene-F₄ antagonists,phosphodiesterase inhibitors, calcium antagonists or PAF antagonists.

EXAMPLE 1(+)-(5RS)-5-Acetoxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-acetoxy-1,3,tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanolNonpolar and Polar Diastereomers

A solution of 16 g of 4-chloro-1-(tert-butyldimethylsilyloxy)-butane in14.4 ml of tetrahydrofuran and 0.84 ml of dibromomethane is instilled in4 g of magnesium at 25° C. under argon, heated for 10 minutes to 70° C.,stirred for 30 minutes at 25° C. and diluted with 45.2 ml oftetrahydrofuran.

A solution of 4.2 g ofcis-(1RS)-1-formyl-(6RS)-6-[(1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-3-cyclohexenein 8.25 ml of tetrahydrofuran is installed in 29.9 ml of this magnesiumorganic solution at -20° C. under argon and stirred for 30 minutes at-20° C. It is mixed with 150 ml of saturated ammonium chloride solution,extracted three times with ether, the organic phase is shaken out withbrine, dried on magnesium sulfate and concentrated by evaporation in avacuum. The residue is chromatographed on silica gel. With hexane/ethylacetate (8+2), 4.1 g of the alcohol is obtained as a colorless oil.

IR (CHCl₃): 3600, 2930, 2858, 1725, 1250, 992, 838 cm⁻¹.

For acetylation, 6.3 ml of acetic anhydride is added to a solution of 6g of the above-described alcohol in 38 ml of pyridine and stirred for 16hours at 24° C. Then, it is concentrated by evaporation in a vacuum withadding toluene and the residue is chromatographed on silica gel. Withhexane/ethyl acetate (95+5), 4.9 g of the acetate is obtained as acolorless oil.

IR: 2930, 2860, 1728, 1255, 991, 838 cm⁻¹.

For cleavage of the protecting groups, 4.55 g of the above-producedacetate in 320 ml of tetrahydrofuran is stirred with 7.5 g oftetrabutylammonium fluoride for 1 hour at 20° C. and for 4 hours at 24°C. under argon. Then, it is diluted with ether, washed three times withwater, dried on magnesium sulfate and concentrated by evaporation in avacuum. The residue is chromatographed with hexane/ethyl acetate (6+4)on silica gel. In this way, first 1.32 g of the nonpolar diastereomerand then 1.7 g of the polar diastereomers of the title compound areobtained as colorless oils.

IR (nonpolar diastereomer); 3630, 3430, 2930, 2860, 1728, 1608, 1375,1250, 992 cm⁻¹.

IR (polar diastereomer); 3630, 3480, 2930, 2860, 1729, 1608, 1375, 1250,992 cm⁻¹.

The initial material for the above-named title compound is produced asfollows:

1a)5-cis-1-(tert-Butyl-dimethylsilyloxymethyl)-3-cyclohexen-6-yl]-(2E,4E)-pentadienoicacid ethyl ester

A solution of 25 g of cis-4-cyclohexene-1,2-dicarboxylic acid anhydridein 140 ml of tetrahydrofuran is instilled in a suspension of 10 g oflithium aluminum hydride in 140 ml of tetrahydrofuran at roomtemperature and the mixture is then stirred for 3 hours at refluxtemperature. It is cooled to 0° C. a mixture of tetrahydrofuran/water(1+1) is instilled slowly, stirred for 30 minutes, mixed with 150 ml ofchloroform, filtered and the filtrate is concentrated by evaporation ina vacuum. The residue is distilled at 0.2 mm/Torr and 150° C. on a bulbtube. After recrystallization of the distillate from toluene/pentane, 21g of cis-1,6-dihydroxymethyl-3-cyclohexene is obtained as colorlesscrystals, melting point 33°-35° C.

19 g of tert-butyldimethylsilyl chloride is added to a solution of 17.7g of the above-produced diol and 17.2 g of imidazole in 147 ml ofdimethylformamide at 0° C. under argon and stirred for 16 hours at 25°C. It is diluted with 1.5 l of ether, shaken out twice with 100 ml of10% sulfuric acid each time, washed neutral with brine, dried onmagnesium sulfate and concentrated by evaporation in a vacuum. Theresidue is chromatographed on silica gel. With hexane/ethyl acetate(9+1), 16.2 g ofcis-1-(tert-butyl-dimethylsilyloxymethyl)-6-hydroxymethyl)-3-cyclohexeneis obtained as a colorless oil.

IR: 3580, 3390, 2930, 2858, 835 cm⁻¹.

140 g of Collins reagent (chromic acid-pyridine complex) is added to asolution of 14 g of the above-described monosilyl ether in 700 ml ofmethylene chloride at 0° C. and stirred for 40 minutes at 0° C. Then, itis diluted with a mixture of hexane/ether (3+2), Celite is added,filtered and concentrated by evaporation in a vacuum. The residue ischromatographed with hexane/ethyl acetate (9+1) on silica gel. In thisway, 12.8 g ofcis-1-(tert-butyl-dimethylsilyloxymethyl)-6-formyl-3-cyclohexene isobtained as a colorless oil.

IR: 2930, 2860, 2730, 1715, 838 cm⁻¹.

For Wittig-Horner olefinization, 12.4 g of phosphonocrotonic acidtriethyl ester and 6.3 g of diazabicycloundecene (DBU) are added at 24°C. to a stirred suspension of 2.1 g of lithium chloride in 412 ml ofacetonitrile and stirred for 10 minutes. Then, a solution of 10.5 g ofthe above-described aldehyde is instilled in 83 ml of acetonitrile,stirred for 3 hours at 24° C. and then diluted with ether. It is shakenout in succession with water, 10% citric acid solution and water, driedon magnesium sulfate and concentrated by evaporation in a vacuum. Theresidue is chromatographed with hexane/ethyl acetate (95+5) on silicagel. In this way, 9 g of the title compound is obtained as a colorlessoil.

IR: 2930, 2858, 1710, 1638, 1618, 1256, 1003, 940, 838 cm⁻¹.

1b)5-[cis-1-(tert-Butyl-dimethylsilyloxymethyl)-3-cyclohexen-6-yl]-(2E,4E)-pentadien-1-al

41 ml of a 1.2 molar solution of diisobutyl aluminum hydride in tolueneis instilled in a solution of 8.8 g of the ester, produced according toexample 1a, in 200 ml of toluene at -70° C. under argon and stirred for40 minutes at -70° C. Then, 4 ml of isopropanol and then 21 ml of wateris instilled, stirred for 2 hours at 22° C. filtered, washed withmethylene chloride and concentrated by evaporation in a vacuum. Theresidue is purified by chromatography on silica gel. With hexane/ethylacetate (8+2), 7.1 g of the alcohol is obtained as a colorless oil.

IR: 3630, 3460, 838 cm⁻¹.

A solution of 7.1 g of the above-produced alcohol in 260 ml of methylenechloride is mixed with 20 g of manganese dioxide and stirred for 4 hoursat 24° C. Then, it is filtered, concentrated by evaporation andchromatographed on silica gel. With hexane/ethyl acetate (85+15), 6.2 gof the title compound is eluted as a colorless oil.

IR: 2930, 2860, 1680, 1638, 990, 950, 838 cm⁻¹.

1c)(5RS)-5-Acetoxy-1-[cis-1-(tert-butyl-dimethylsilyloxymethyl)-3-cyclohexen-6-yl]-(1E,3E)-tridecadiene

A solution of 7.95 ml of octyl bromide in 12 ml of ether is instilled in1.2 g of magnesium in 5 ml of ether with heating and stirred for 30minutes at 25° C.

A solution of 3.0 g of the aldehyde, produced according to example 1b,in 48 ml of ether is installed in 5.85 ml (=10.77 mmol) of this Grignardsolution at -20° C. under argon and stirred for 3 hours at -20° C. It ismixed with saturated ammonium chloride solution, extracted three timeswith ether, the organic phase is shaken out with brine, dried onmagnesium sulfate and concentrated by evaporation in a vacuum. Theresidue is chromatographed on silica gel. With hexane/ethyl acetate(7+3), 3.35 g of the alcohol is eluted as a colorless oil.

IR: 3620, 3460, 2930, 2858, 992, 838.

For acetylation, 6 ml of acetic anhydride is added to a solution of 3.3g of the above-produced alcohol in 12 ml of pyridine and stirred for 16hours at 24° C. Then, it is concentrated by evaporation in a vacuum withthe addition of toluene and the residue is chromatographed on silicagel. With hexane/ethyl acetate (8+21), 3.3 g of the title compound isobtained as an oil.

IR: 2930, 2858, 1730, 1254, 990, 838 cm⁻¹.

1c)(5RS)-5-Acetoxy-1-[cis-1-(tert-butyl-dimethylsilyloxymethyl)-3-cyclohexen-6-yl]-(1E,3E)-tridecadiene

A solution of 7.95 ml of octyl bromide in 12 ml of ether is instilled in1.2 g of magnesium in 5 ml of ether with heating and stirred for 30minutes at 25° C.

A solution of 3.0 g of aldehyde, produced according to example 16, in 48ml of ether is installed in 5.85 ml (=10.77 mmol) of this Grignardsolution at -20° C. under argon and stirred for 3 hours at -20° C. It ismixed with saturated ammonium chloride solution, extracted three timeswith ether, the organic phase is shaken out with brine, dried onmagnesium sulfate and concentrated by evaporation in a vacuum. Theresidue is chromatographed on silica gel. With hexane/ethyl acetate(7+3), 3.35 g of the alcohol is eluted as a colorless oil.

IR: 3620, 3460, 2930, 2858, 992, 838.

For acetylation, 6 ml of acetic anhydride is added to a solution of 3.3g of the above-produced alcohol in 12 ml of pyridine and stirred for 16hours at 24° C. Then, it is concentrated by evaporation in a vacuum withthe addition of toluene and the residue is chromatographed on silicagel. With hexane/ethyl acetate (8+2), 3.3 g of the title compound isobtained as an oil.

IR: 2930, 2858, 1730, 1254, 990, 838 cm⁻¹.

1d)cis-1RS)-1-Formyl-(6RS)-6-[(1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-3-cyclohexene

6.55 g of tetrabutylammonium fluoride is added to a solution of 3.2 g ofthe acetate, produced according to example 1c), in 320 ml oftetrahydrofuran at 0° C., stirred for 1 hour at 0° C. and for 3 hours at24° C. Then, it is diluted with 1.2 l of ether and washed three timeswith brine. It is dried on magnesium sulfate, concentrated byevaporation in a vacuum, and the residue is chromatographed on silicagel. With hexane/ethyl acetate (6+4), 2.4 g of the alcohol is eluted asa colorless oil.

IR: 3620, 3460, 2930, 2860, 1722, 1250, 991 cm⁻¹.

19 g of Collins reagent (chromic acid-pyridine complex) is added to asolution of 2.71 g of the above-produced alcohol in 7 5ml of methylenechloride at 0° C. and stirred for 15 minutes at 0° C. Then, it isdiluted with a mixture of hexane/ether (3+2), Celite is added, filteredand concentrated by evaporation in a vacuum. The aldehyde thus obtainedis used without further purification.

EXAMPLE 2(+)-(5RS)-5-Acetoxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Diastereomer A

1.92 g of Collins reagent is added to a solution of 350 mg of thenonpolar diastereomeric diacetate, described in example 1, in 28 ml ofmethylene chloride at 0° C. and stirred for 15 minutes at 0° C. Then, itis diluted with a mixture of hexane/ether (3+2), Celite is added,filtered, washed with hexane/ether (3+2) and concentrated by evaporationin a vacuum.

0.7 ml of Jones reagent (J. Chem. Soc., 1953, 2555) is instilled in asolution of 360 mg of the above-produced aldehyde in 12.5 ml of acetonewith stirring at -20° C. and stirred for 12 minutes at -20° C. underargon. Then, 3 ml of isopropanol is added, stirred for 10 minutes,diluted with 40 ml of ether, filtered, washed with ether, the etherphase is shaken out twice with brine, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. The residue is chromatographedon silica gel. With hexane/ethyl acetate (6+4), 290 mg of the titlecompound is obtained as a colorless oil.

IR: 3520 (broad), 2928, 2859, 1725, 1372, 1250, 991, 948 cm⁻¹.

EXAMPLE 3(+)-(RS)-5-Hydroxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Diastereomer A

60 mg of the nonpolar diastereomeric diacetate (diastereomer A)described in example 2 is stirred for 48 hours at 24° C. with 2.5 ml ofa solution of potassium hydroxide in water and ethanol (production: 5 gof potassium hydroxide is dissolved in 67.5 ml of water and 182.5 ml ofethanol). Then, it is acidified with 10% citric acid solution to pH 4,extracted four times with 15 ml of methylene chloride each, the organicphase is shaken out with brine, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. The residue is chromatographedwith ethyl acetate/hexane (8+2) on silica gel. In this way, 41 mg of thetitle compound is obtained as a colorless oil.

IR: 3600, 3400 (broad), 2930, 2859, 1720, 1375, 992 cm⁻¹.

EXAMPLE 4(+)-(5RS)-5-Acetoxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Diastereomer A

1.5 ml of a 0.5 normal sodium hydroxide solution is added to a solutionof 70 mg of the nonpolar diastereomeric diacetate (diastereomer A),produced according to example 2, in 1.5 ml of methanol at 24° C. andstirred for 7 hours at 24° C. under argon. Then, it is diluted with 2 mlof water and acidified at ice bath temperature with 10% citric acidsolution to pH 4. It is extracted four times with 30 ml of ethyl acetateeach, the organic phase is shaken out with brine, dried on magnesiumsulfate and concentrated by evaporation in a vacuum. The residue ischromatographed on silica gel. With ether/hexane (1+1), 51 mg of thetitle compound is obtained as a colorless oil.

IR: 3600, 3450, 2930, 2859, 1722, 1375, 1250, 992 cm⁻¹.

EXAMPLE 5

(30)-(5RS)-5-Hydroxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoldiastereomer A

88 mg of the nonpolar diastereomeric diacetate described in example 1 isstirred for 60 hours at 24° C. with 2.7 ml of a solution of potassiumhydroxide in water and ethanol (production: 5 g of potassium hydroxideis dissolved in 67.5 ml of water and 182.5 ml of ethanol). Then, it isacidified with 10% citric acid solution to pH 6, extracted four timeswith 20 ml of methylene chloride each, the organic phase is shaken outwith brine, dried on magnesium sulfate and concentrated by evaporationin a vacuum. The residue is chromatographed with ethyl acetate on silicagel. In this way, 48 mg of the title compound is obtained as a colorlessoil.

IR: 3620, 3380 (broad), 2929, 2860, 992 cm⁻¹.

EXAMPLE 6(+)-(5RS)-5-Acetoxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanolDiastereomer A

58 mg of the nonpolar diastereomeric diacetate, described in example 1,in 1.4 ml of methanol is stirred for 4 hours at 24° C. with 1.4 ml of a0.5 normal sodium hydroxide solution under argon. Then, it is dilutedwith 5 ml of water, neutralized with 10% citric acid solution, extractedfour times with 20 ml of methylene chloride each, the organic phase isshaken out with brine, dried n magnesium sulfate and concentrated byevaporation in a vacuum. The residue is chromatographed with ethylacetate/hexane (1+1) on silica gel. In this way, 21 mg of the titlecompound is obtained as a colorless oil.

IR: 3600, 3450 (broad), 2930, 2860, 1730, 1375, 1252, 993 cm⁻¹.

EXAMPLE 7(+)-(5RS)-5-Acetoxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Diastereomer B

Analogously to example 2, 315 mg of the title compound is obtained as acolorless oil from 425 mg of the polar diastereomeric diacetate producedaccording to example 1.

IR: 3515 (broad), 2928, 2859, 1725, 1372, 1250, 991, 948 cm⁻¹.

EXAMPLE 8(+)-(5RS)-5-Hydroxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Diastereomer B

Analogously to example 3, 240 mg of the title compound is obtained as acolorless oil from 320 mg of the diacetate (diastereomer B) producedaccording to example 7.

IR: 3600, 3420 (broad), 2930, 2860, 1720, 1375, 992 cm⁻¹.

EXAMPLE 9(+)-(4RS)-5-Acetoxy-5-[cis-(6RS-6-((1E,3E)-(4RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Diastereomer B

Analogously to example 4, 70 mg of the title compound is obtained as acolorless oil from 130 mg of the diacetate (diastereomer B) producedaccording to example 7.

IR: 3620, 3400 (broad), 2930, 2859, 1722, 1375, 1250, 992 cm⁻¹.

EXAMPLE 10(+)-(5RS)-5-Hydroxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanolDiastereomer B

Analogously to example 5, 81 mg of the title compound is obtained as acolorless oil from 145 mg of the polar diastereomeric diacetate producedin example 1.

IR: 3600, 3400 (broad), 2930, 2860, 992 cm⁻¹.

EXAMPLE 11(+)-(5RS)-5-Acetoxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanolDiastereomer B

Analogously to example 6, 40 mg of the title compound is obtained as acolorless oil from 70 mg of the polar diastereomeric diacetate producedin example 1.

IR: 3620, 3430 (broad), 2930, 2860, 1730, 1375, 1250, 993 cm⁻¹.

EXAMPLE 12(+)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanolNonpolar and Polar Diastereomers

Analogously to example 1, 1.2 g of the nonpolar diastereomer and 1.3 gof the polar diastereomer of the title compound are obtained ascolorless oils from 4 g ofcis-(1RS)-1-formyl-(2RS)-2-[(1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]cyclohexane.

IR (nonpolar diastereomer); 3620, 3420, 2929, 2859, 1729, 1607, 1375,1250, 992 cm⁻¹.

IR (polar diastereomer) 3600, 3430, 2929, 2860, 1729, 1607, 1375, 1250,992 cm⁻¹.

The initial material for the above title compound is produced asfollows:

12a)5-[cis-1-(tert-Butyl-dimethylsilyloxymethyl)-cyclohex-2-yl]-(2E,4E)-pentadienoicAcid Ethyl Ester

Analogously to example 1a), the title compound is obtained as acolorless oil from cis-1,2-dihydroxymethyl-cyclohexane.

IR: 2929, 2859, 1710, 1638, 1618, 1255, 1004, 940, 838 cm⁻¹.

12b)5-[cis-1-(tert-Butyl-dimethylsilyloxymethyl)-cyclohex-2-yl]-(2E,4E)pentadien-1-al

Analogously to example 1b), 13 g of the title compound is obtained as acolorless oil from 16 g of the ester produced according to example 12a).

IR: 2930, 2859, 1680, 1640, 992, 950, 840 cm⁻¹.

12c)(5RS)-5-Acetoxy-1-[cis-1-(tert-butyl-dimethylsilyloxymethyl)-cyclohex-1-yl]-(1E,3E)-tridecadiene

Analogously to example 1c), 3.8 g of the title compound is obtained as acolorless oil from 4.2 g of the aldehyde produced according to example12b).

IR: 2928, 2859, 1730, 1255, 990 838 cm⁻¹.

12d)cis-(1RS)-1-Formyl-(2RS)-2-[(1E,3E)-(5RS)-5-acetoxy-1,3tridecadienyl]-cyclohexane

Analogously to example 1d, 2.9 g of the aldehyde is obtained as crudeproduce from 4.2 g of the acetate produced according to example 12c).

EXAMPLE 13(+)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer A

Analogously to example 2, 230 mg of the title compound is obtained as acolorless oil from 335 mg of the nonpolar diastereomeric diacetateproduced according to example 12.

IR: 3520 (broad), 2930, 2860, 1725, 1373, 1251, 991, 948 cm⁻¹.

EXAMPLE 14(+)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer A

Analogously to example 3, 253 mg of the title compound is obtained as acolorless oil from 390 mg of the diacetate (diastereomer A) producedaccording to example 13.

IR: 3600, 3410 (broad), 2930, 2860, 1720, 1375, 993 cm⁻¹.

EXAMPLE 15(+)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-)1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer A

Analogously to example 4, 77 mg of the title compound is obtained as acolorless oil from 110 mg of the diacetate (diastereomer A) producedaccording to example 13.

IR: 3600, 3430, 2929, 2858, 1722, 1375, 1250, 992 cm⁻¹.

EXAMPLE 16(+)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer B

Analogously to example 2, 190 mg of the title compound is obtained as acolorless oil from 270 mg of the polar diastereomeric diacetate producedaccording to example 12.

IR: 3600 (broad), 2930, 2859, 1725, 1375, 1250, 991, 948 cm⁻¹.

EXAMPLE 17(+)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer B

Analogously to example 3, 185 mg of the title compound is obtained as acolorless oil from 280 mg of the diacetate (diastereomer B) producedaccording to example 16.

IR: 3610, 3415 (broad), 2930, 2860, 1720, 1375, 993 cm⁻¹.

EXAMPLE 18(+)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer B

Analogously to example 4, 80 mg of the title compound is obtained as acolorless oil from 140 mg of the diacetate (diastereomer B) producedaccording to example 16.

IR: 3600, 3420, 2930, 2859, 1722, 1376, 1251, 992 cm⁻¹.

EXAMPLE 19(+)-(5RS)-5-Acetoxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Methyl Ester Diastereomer A

An ethereal diazomethane solution is instilled until permanent yellowcoloring in a solution of 51 mg of the acid, produced according toexample 2, in 5 ml of methylene chloride at 0° C. and stirred for 15minutes at 0° C. Then, it is concentrated by evaporation in a vacuum andthe residue is chromatographed on silica gel. With hexane/ethyl acetate(9+1), 48 mg of the title compound is obtained as a colorless oil.

IR (film): 2923, 2851, 1739, 1655, 1370, 1240, 990 cm⁻¹.

EXAMPLE 20 (+)-(5RS)-5-Hydroxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Methyl Ester Diastereomer A

An ethereal diazomethane solution is instilled until permanent yellowcoloring in a solution of 40 mg of the acid, produced according toexample 3, in 4 ml of methylene chloride at 0° C. and stirred for 15minutes at 0° C. Then, it is concentrated by evaporation in a vacuum,and the residue is chromatographed on silica gel. With hexane/ethylacetate (1+9), 32 mg of the title compound is obtained as a colorlessoil.

IR (film): 3610, 2922, 2853, 1737, 1655, 1435, 990 cm⁻¹.

EXAMPLE 21(+)-(5RS)-5-Acetoxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Methyl Ester Diastereomer A

An ethereal diazomethane solution is instilled until permanent yellowcoloring in a solution of 38 mg of the acid, produced according toexample 4, in 4 ml of methylene chloride at 0° C. and stirred for 15minutes at 0° C. Then, it is concentrated by evaporation in a vacuum,and the residue is chromatographed on silica gel. With hexane/ethylacetate (1+1), 30 mg of the title compound is obtained as a colorlessoil.

IR (film); 3420, 2923, 2858, 1739, 1655, 1370, 1240, 990 cm⁻¹.

EXAMPLE 22(+)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Methyl Ester Diastereomer A

Analogously to example 19, 71 mg of the title compound is obtained as acolorless oil from 85 mg of the acid produced according to example 13.

IR (film): 2924, 2852, 1739, 1655, 1371, 1240, 991 cm⁻¹.

EXAMPLE 23(+)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Methyl Ester Diastereomer A

Analogously to example 20, 65 mg of the title compound is obtained as acolorless oil from 73 mg of the acid produced according to example 14.

IR (film): 3600, 2922, 2852, 1738, 1655, 1436, 991 cm⁻¹.

EXAMPLE 24(+)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Methyl Ester Diastereomer A

Analogously to example 21, 40 mg of the title compound is obtained as acolorless oil from 45 mg of the acid produced according to example 15.

IR (film): 3430, 2924, 2859, 1739, 1655, 1370, 1240, 990 cm⁻¹.

EXAMPLE 25(+)-(5RS)-5-Hydroxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid-1,5-lactone Diastereomer A

1 g of anhydrous magnesium sulfate is added in portions to a solution of40 mg of the acid, produced according to example 3, in 8 ml of tolueneat 24° C. over a period of 24 hours and stirred for another 24 hours at24° C. Then, it is filtered and the evaporation residue ischromatographed on silica gel. With toluene/ethyl acetate (7+3), 22 mgof the lactone is eluted as a colorless oil.

IR (CHCl₃): 3600, 2930, 2860, 1725, 1248, 1045, 992 cm⁻¹.

EXAMPLE 26(+)-(5RS)-5-Hydroxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid-1,5-lactone Diastereomer B

Analogously to example 25, 32 mg of the title compound is obtained as acolorless oil from 67 mg of the acid produced according to example 8.

IR (CHCl₃): 3600, 2929, 2860, 1725, 1248, 1045, 992 cm⁻¹.

EXAMPLE 27(+)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid-1,5-lactone Diastereomer A

Analogously to example 25, 52 mg of the title compound is obtained as acolorless oil from 120 mg of the acid produced according to example 14.

IR (CHCl₃): 3620, 2930, 2860, 1725, 1248, 1046, 993 cm⁻¹.

EXAMPLE 28(+)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid-1,5-lactone Diastereomer B

Analogously to example 25, 41 mg of the title compound is obtained as acolorless oil from 80 mg of the acid produced according to example 17.

IR (CHCl₃): 3600, 2930, 2860, 1726, 1248, 1046, 993 cm⁻¹.

EXAMPLE 29(+)-(5RS)-5-Hydroxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid-tris-(hydroxymethyl)-aminomethane Salt

A solution of 14 mg of tris-(hydroxymethyl)-aminomethane in 0.04 ml ofwater is added to a solution of 38 mg of the carboxylic acid, producedaccording to example 3, in 6 ml of acetonitrile at 70° C. It is allowedto cool with stirring, decanted after 16 hours from the solvent and theresidue is dried in a vacuum. 25 mg of the title compound is isolated asa wavy mass.

EXAMPLE 30(+)-(5RS)-5-Acetoxy-5-[trans(4RS)-6-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1yl]-pentanolNonpolar and Polar Diastereomers

A solution of 16.7 g of 4-chloro-1-(tert-butyldimethylsilyloxy)-butanein 15 ml of tetrahydrofuran and 0.45 ml of dibromomethane is instilledin 3.65 g of magnesium at 25° C. under argon, heated for 10 minutes to70° C., stirred for 30 minutes at 25° C. and diluted with 45.2 ml oftetrahydrofuran.

A solution of 1.95 g oftrans-(1RS)-1-formyl-(6RS)-6-[(1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-3-cyclohexenein 5 ml of tetrahydrofuran is instilled in 10 ml of this magnesiumorganic solution at -20° C. under argon and stirred for 30 minutes at-20° C. It is mixed with 100 ml of saturated ammonium chloride solution,extracted three times with ether, the organic phase is shaken out withbrine, dried on magnesium sulfate and concentrated by evaporation in avacuum. The residue is chromatographed on silica gel. With hexane/ethylacetate (8+2), 1.85 g of the alcohol is obtained as a colorless oil.

IR (CHCl₃): 3600, 2930, 2860, 1725, 1252, 992, 838 cm⁻¹.

For acetylation, 5 ml of acetic anhydride is added to a solution of 1.5g of the above-described alcohol in 30 ml of pyridine and stirred for 16hours at 24° C. Then, it is concentrated by evaporation with theaddition of toluene in a vacuum, and the residue is chromatographed onsilica gel. With hexane/ethyl acetate (95+5), 1.64 g of the acetate isobtained as a colorless oil.

IR: 2930, 2860, 1728, 1255, 990, 838 cm⁻.

For cleavage of protecting groups, 1.2 g of the above-produced acetateis stirred in 85 ml of tetrahydrofuran with 2.0 g of tetrabutylammoniumfluoride for 1 hour at 0° C. and for 4 hours at 24° C. under argon.Then, it is diluted with ether, washed three times with water, dried onmagnesium sulfate and concentrated by evaporation in a vacuum. Theresidue is chromatographed with hexane/ethyl acetate (6+4) on silicagel. In this way, 0.45 g of the nonpolar diastereomer is obtained firstand then 0.4 g of the polar diastereomer of the title compound ascolorless oils.

IR (nonpolar diastereomer): 3600, 3430, 2930, 2858, 1728, 1608, 1375,1250, 992 cm⁻¹.

IR (polar diastereomer): 3620, 3480, 2930, 2860, 1729, 1608, 1375, 1250,992 cm⁻¹.

The initial material for the above-named title compound is produced asfollows:

30a)5-[trans-1-(tert-Butyl-dimethylsilyloxymethyl)-3-cyclohexen-6-yl]-(2E,4E)-pentadienoicacid ethyl ester

A solution of 25 g of trans-4-cyclohexene-1,2-dicarboxylic acid diethylester in 140 ml of tetrahydrofuran is instilled in a suspension of 10 gof lithium aluminum hydride in 140 ml of tetrahydrofuran at roomtemperature and the mixture is then stirred for 3 hours at refluxtemperature. It is cooled to 0° C., a mixture of tetrahydrofuran/water(1+1) is instilled slowly, stirred for 30 minutes, mixed with 150 ml ofchloroform, filtered and the filtrate is concentrated by evaporation ina vacuum. The residue is distilled at 0.2 mm/Hg and at 150° C. in a bulbtube. In this way, 20 g of trans-1,6-dihydroxymethyl-3-cyclohexene isobtained as a colorless oil.

10.6 g of tert-butyldimethylsilyl chloride is added to a solution of 10g of the above-produced diol and 9.6 g of imidazole in 93 ml ofdimethylformamide at 0° C. under argon and stirred for 16 hours at 25°C. It is diluted with 0.6 l of ether, shaken twice with 100 ml of 10%sulfuric acid each, washed neutral with brine, dried on magnesiumsulfate and concentrated by evaporation in a vacuum. The residue ischromatographed on silica gel. With hexane/ethyl acetate (9+1), 7.3 g oftrans-1-(tert-butyl-dimethylsilyloxymethyl)-6-hydroxymethyl-3-cyclohexeneis obtained as a colorless oil.

IR: 3600, 3390, 2930, 2858, 835 cm⁻¹.

45 g of Collins reagent (chromic acid-pyridine complex) is added to asolution of 6.6 g of the above-described monosilyl ether in 350 ml ofmethylene chloride at 0° C. and stirred for 40 minutes at 0° C. Then, itis diluted with a mixture of hexane/ether (3+2), Celite is added,filtered and concentrated by evaporation in a vacuum. The residue ischromatographed with hexane/ethyl acetate (9+1) on silica gel. In thisway, 5.5 g oftrans-1-(tert-butyl-dimethylsilyloxymethyl)-6-formyl-3-cyclohexene isobtained as a colorless oil.

IR: 2930, 2860, 2730, 1716, 838 cm⁻¹.

For Wittig-Horner olefinization, 4.6 g of phosphonocrotonic acidtriethyl ester and 2.3 g of diazabicycloundecene (DBU) are added at 24°C. to a stirred suspension of 0.78 g of lithium chloride in 153 ml ofacetonitrile and stirred for 10 minutes. Then, a solution of 3.9 g ofthe above-described aldehyde is instilled in 31 ml of acetonitrile,stirred for 3 hours at 24° C. and then diluted with ether. It is shakenout in succession with water, 10% citric acid solution and water, driedon magnesium sulfate and concentrated by evaporation in a vacuum. Theresidue is chromatographed with hexane/ethyl acetate (95+5) on silicagel. In this way, 4.1 g of the title compound is obtained as a colorlessoil.

IR: 2930, 2858, 1710, 1638, 1618, 1256, 1003, 940, 838 cm⁻¹.

30b)5-[trans-1-(tert-Butyl-dimethylsilyloxymethyl)-3-cyclohexen-6-yl]-(2E,4E)-pentadien-1-al

16.6 ml of a 1.2 molar solution of diisobutyl aluminum hydride intoluene is instilled in a solution of 3.5 g of the ester, producedaccording to example 30a), in 94 ml of toluene at -70° C. under argonand stirred for 40 minutes at -70° C. Then, 2 ml of isopropanol and then8 ml of water are instilled, stirred for 2 hours at 22° C., filtered,washed with methylene chloride and concentrated by evaporation in avacuum. The residue is purified by chromatography on silica gel. Withhexane/ethyl acetate (8+2), 3.04 g of the alcohol is obtained as acolorless oil. IR: 3620, 3460, 838 cm⁻¹.

A solution of 3.02 g of the above-produced alcohol in 110 ml of tolueneis mixed with 8.5 g of manganese dioxide and stirred for 4.5 hours at24° C. Then, it is filtered, concentrated by evaporation andchromatographed on silica gel. With hexane/ethyl acetate (85+15), 2.9 gof the title compound is eluted as a colorless oil.

IR: 2929, 2860, 1680, 1638, 992, 950, 838 cm⁻¹.

30c)(5RS)-5-Acetoxy-1-[trans-1-(tert-butyl-dimethylsilyloxymethyl)-3-cyclohexen-6yl]-(1E,3E)-tridecadiene

A solution of 7.95 ml of octyl bromide in 12 ml of ether is instilled in1.2 g of magnesium in 5 ml of ether with heating and stirred for 30minutes at 25° C.

A solution of 2.85 g of the aldehyde, produced according to example30b), in 47 ml of ether is instilled in 5.85 ml (32 10.77 mmol) of thisGrignard solution at -20° C. under argon and stirred for 3 hours at -20°C. It is mixed with saturated ammonium chloride solution, extractedthree times with ether, the organic phase is shaken out with brine,dried on magnesium sulfate and concentrated by evaporation in a vacuum.The residue is chromatographed on silica gel. With hexane/ethyl acetate(7+3), 2.92 g of the alcohol is eluted as a colorless oil.

IR: 3620, 3460, 2929, 2858, 992, 838.

For acetylation, 5 ml of acetic anhydride is added to a solution of 3.0g of the above-produced alcohol in 30 ml of pyridine and stirred for 16hours at 24° C. Then, it is concentrated by evaporation with theaddition of toluene in a vacuum, and the residue is chromatographed onsilica gel. With hexane/ethyl acetate (8+2), 3.25 g of the titlecompound is obtained as oil.

IR: 2930, 2858, 1730, 1254, 990, 838 cm⁻¹.

30d)trans-(1RS)-1-Formyl-(6RS)-6-[(1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-3-cyclohexene

6.55 g of tetrabutylammonium fluoride is added to a solution of 3.2 g ofthe acetate, produced according to example 30c), in 320 ml oftetrahydrofuran at 0° C., stirred for 1 hour at 0° C. and for 3 hours at24° C. Then, it is diluted with 1.2 l of ether and washed three timeswith brine. It is dried on magnesium sulfate, concentrated byevaporation in a vacuum and the residue is chromatographed on silicagel. With hexane/ethyl acetate (6+4), 2.34 g of the alcohol is eluted asa colorless oil.

IR: 3620, 3458, 2930, 2860, 1722, 1250, 991 cm⁻¹.

18 g of Collins reagent ()chromic acid-pyridine complex) is added to asolution of 2.46 g of the above-produced alcohol in 70 ml of methylenechloride at 0° C. and stirred for 15 minutes at 0° C. Then, it isdiluted with a mixture of hexane/ether (3+2), Celite is added, filteredand concentrated by evaporation in a vacuum. The aldehyde thus obtainedis used without further purification.

EXAMPLE 31(+)-(5RS)-5-Acetoxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohexen-1yl]-pentanoicAcid Diastereomer A

1.98 g of Collins reagent is added to a solution of 360 mg of thenonpolar diastereomeric diacetate, described in example 30, in 28 ml ofmethylene chloride at 0° C. and stirred for 15 minutes at 0° C. Then, itis diluted with a mixture of hexane/ether (3+2), Celite is added,filtered, washed with hexane/ether (3+2) and concentrated by evaporationin a vacuum.

0.7 ml of Jones reagent (J. Chem. Soc. 1953, 2555) is instilled in asolution of 380 mg of the above-produced aldehyde in 12.5 ml of acetonewith stirring at -20° C. and stirred for 12 minutes at -20° C. underargon. Then, 3 ml of isopropanol is added, it is stirred for 10 minutes,diluted with 40 ml of ether, filtered, washed with ether, the etherphase is shaken out twice with brine, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. The residue is chromatographedon silica gel. With hexane/ethyl acetate (6+4), 280 mg of the titlecompound is obtained as a colorless oil.

IR: 3520 (broad), 2928, 2859, 1725, 1372, 1250, 991, 948 cm⁻¹.

EXAMPLE 32(+)-(RS)-5-Hydroxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Diastereomer A

68 mg of the nonpolar diastereomeric diacetate (diastereomer A)described in example 31 is stirred for 48 hours at 24° C. with 2.5 ml ofa solution of potassium hydroxide in water and ethanol (production: 5 gof potassium hydroxide is dissolved in 67.5 ml of water and 182.5 ml ofethanol). Then, it is acidified with 10% citric acid solution to pH 4,extracted four times with 15 ml of methylene chloride each, the organicphase is shaken out with brine, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. The residue is chromatographedwith ethyl acetate/hexane (8+2) on silica gel. In this way, 41 mg of thetitle compound is obtained as a colorless oil.

IR: 3620, 3415 (broad), 2929, 2859, 1720, 1375, 992 cm⁻¹.

EXAMPLE 33(+)-(5RS)-5-Acetoxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Diastereomer A

1.5 ml of a 0.5 normal sodium hydroxide solution is added to a solutionof 72 mg of the nonpolar diastereomeric diacetate (diastereomer A),produced according to example 31, in 1.5 ml of methanol at 24° C. andstirred for 7 hours at 24° C. under argon. Then, it is diluted with 2 mlof water and acidified at ice bath temperature with 10% citric acidsolution to pH 4. It is extracted four times with 30 ml of ethyl acetateeach, the organic phase is shaken out with brine, dried on magnesiumsulfate and concentrated by evaporation in a vacuum. The residue ischromatographed on silica gel. With ether/hexane (1+1), 51 mg of thetitle compound is obtained as a colorless oil.

IR: 3615, 3450, 2930, 2859, 1721, 1375, 1250, 992 cm⁻¹.

EXAMPLE 34(+)-(5RS)-5-Hydroxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanolDiastereomer A

98 mg of the nonpolar diastereomeric diacetate described in example 30is stirred for 60 hours at 24° C. with 2.9 ml of a solution of potassiumhydroxide in water and ethanol (production: 5 g of potassium hydroxideis dissolved in 67.5 ml of water and 182.5 ml of ethanol). Then, it isacidified with 10% citric acid solution to pH 6, extracted four timeswith 20 ml of methylene chloride each, the organic phase is shaken outwith brine, dried on magnesium sulfate and concentrated by evaporationin a vacuum. The residue is chromatographed with ethyl acetate on silicagel. In this way, 58 mg of the title compound is obtained as a colorlessoil.

IR: 3600, 3380 (broad), 2930, 2860, 992 cm⁻¹.

EXAMPLE 35(+)-(5RS)-5-Acetoxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanolDiastereomer A

60 mg of the nonpolar diastereomeric diacetate, described in example 30,in 1.4 ml of methanol is stirred for 4 hours at 24° C. with 1.4 ml of a0.5 normal sodium hydroxide solution under argon. Then, it is dilutedwith 5 ml of water, neutralized with 10% citric acid solution, extractedfour times with 20 ml of methylene chloride each, the organic phase isshaken out with brine, dried on magnesium sulfate and concentrated byevaporation in a vacuum. The residue is chromatographed with ethylacetate/hexane (1+1) on silica gel. In this way, 21 mg of the titlecompound is obtained as a colorless oil.

IR: 3600, 3450 (broad), 2929, 2860, 1730, 1375, 1252, 993 cm⁻¹.

EXAMPLE 36(+)-(5RS)-5-Acetoxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Diastereomer B

Analogously to example 31, 300 mg of the title compound is obtained as acolorless oil from 405 mg of the polar diastereomeric diacetate producedaccording to example 30.

IR: 3515 (broad), 2929, 2860, 1725, 1372, 1250, 991, 948 cm⁻.

EXAMPLE 37(+)-(5RS)-5-Hydroxy-5-[trans-(6RS)-6((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Diastereomer B

Analogously to example 32, 160 mg of the title compound is obtained as acolorless oil from 220 mg of the diacetate (diastereomer B) producedaccording to example 36.

IR: 3600, 3420 (broad), 2930, 2860, 1721, 1375, 992 cm⁻¹.

EXAMPLE 38(+)-(5RS)-5-Acetoxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Diastereomer B

Analogously to example 33, 60 mg of the title compound is obtained as acolorless oil from 120 mg of the diacetate (diastereomer B) producedaccording to example 36.

IR: 3620, 3400 (broad), 2930, 2860, 1722, 1375, 1250, 992 cm⁻¹.

EXAMPLE 39(+)-(5RS)-5-Hydroxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanolDiastereomer B

Analogously to example 34, 72 mg of the title compound is obtained as acolorless oil from 140 mg of the polar diastereomeric diacetate producedin example 30.

IR: 3600, 3420 (broad), 2930, 2860, 992 cm⁻¹.

EXAMPLE 40(+)-(5RS)-5-Acetoxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanolDiastereomer B

Analogously to example 35, 30 mg of the title compound is obtained as acolorless oil from 50 mg of the polar diastereomeric diacetate producedin example 30.

IR: 3620, 3430 (broad), 2930, 2860, 1729, 1376, 1250, 993 cm⁻¹.

EXAMPLE 41(+)-(5RS)-5-Acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanolNonpolar and Polar Diastereomer

Analogously to example 30, 0.5 g of nonpolar diastereomer and 0.6 g ofpolar diastereomer of the title compound are obtained as colorless oilsfrom 2 g oftrans-(1RS)-1-formyl-(2RS)-2-[(1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-cyclohexane.

IR (nonpolar diastereomer): 3620, 3420, 2929, 2859, 1729, 1607, 1375,1250, 992 cm⁻.

IR (polar diastereomer): 3600, 3430, 2929, 2860, 1729, 1607, 1375, 1250,992 cm⁻¹.

The initial material for the above-named title compound is produced asfollows:

41a)5-[trans-1-(tert-Butyl-dimethylsilyloxymethyl)-cyclohex-2-yl]-(2E,4E)-pentadienoicacid ethyl ester

Analogously to example 30a, the title compound is obtained as acolorless oil from trans-1,2-dihydroxymethylcyclohexane.

IR: 2930, 2859, 1710, 1638, 1618, 1255, 1004, 940, 838 cm⁻¹.

41b)5-[trans-1-(tert-Butyl-dimethylsilyloxymethyl)-cyclohex-2-yl]-(2E,4E)-pentadien-1-al

Analogously to example 30b), 28 g of the title compound is obtained as acolorless oil from 33 g of the ester produced according to example 41a).

IR: 2930, 2859, 1680, 1640, 993, 950, 840 cm⁻¹.

41c)(5RS)-5Acetoxy-1-[trans-1-(tert-butyl-dimethylsilyloxymethyl)-cyclohex-1-yl]-(1E,3E)-tridecadiene

Analogously to example 30c), 7.5 g of the title compound is obtained asa colorless oil from 8.3 g of the aldehyde produced according to example42b).

IR: 2930, 2860, 1731, 1255, 993, 838 cm⁻¹.

41d)trans-(1RS)-1-Formyl-(2RS)2-[(1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-cyclohexane

Analogously to example 30d), 3.0 g of the aldehyde is obtained as crudeproduct from 4.3 g of the acetate produced according to example 30c).

EXAMPLE 42(+)-(5RS)-5-Acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer A

Analogously to example 31, 390 mg of the title compound is obtained as acolorless oil from 500 mg of the nonpolar diastereomeric diacetateproduced according to example 41.

IR: 3500 (broad), 2930, 2860, 1725, 1373, 1251, 991, 948 cm⁻¹.

EXAMPLE 43(+)-(5RS)-5-Hydroxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid diastereomer A

Analogously to example 32, 203 mg of the title compound is obtained as acolorless oil from 300 mg of the diacetate (diastereomer A) producedaccording to example 42.

IR: 3620, 3410 (broad), 2930, 2859, 1720, 1375, 993 cm⁻¹.

EXAMPLE 44(+)-(5RS)-5-Acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer A

Analogously to example 33, 70 mg of the title compound is obtained as acolorless oil from 120 mg of the diacetate (diastereomer A) producedaccording to example 42.

IR: 3620, 3430, 2929, 2859, 1722, 1375, 1250, 992 cm⁻¹.

EXAMPLE 45(+)-(5RS)-5-Acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer B

Analogously to example 31, 180 mg of the title compound is obtained as acolorless oil from 290 mg of the polar diastereomeric diacetate producedaccording to example 41.

IR: 3620 (broad), 2930, 2860, 1725, 1375, 1250, 991, 948 cm⁻¹.

EXAMPLE 46(+)-(5RS)-5-Hydroxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer B

Analogously to example 32, 205 mg of the title compound is obtained as acolorless oil from 310 mg of the diacetate (diastereomer B) producedaccording to example 45.

IR: 3620, 3415 (broad), 2930, 2860, 1720, 1375, 993 cm⁻¹.

EXAMPLE 47(+)-(5RS)-5-Acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1yl]-pentanoicAcid Diastereomer B

Analogously to example 33, 70 mg of the title compound is obtained as acolorless oil from 150 mg of the diacetate (diastereomer B) producedaccording to example 45.

IR: 3600, 3410, 2930, 2860, 1722, 1376, 1251, 992 cm⁻¹.

EXAMPLE 48(+)-(5RS)-5-Acetoxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Methyl Ester Diastereomer A

An ethereal diazomethane solution is instilled until permanent yellowcoloring in a solution of 150 mg of the acid, produced according toexample 31, in 15 ml of methylene chloride at 0° C. and stirred for 15minutes at 0° C. Then, it is concentrated by evaporation in a vacuum,and the residue is chromatographed on silica gel. With hexane/ethylacetate (9+1), 140 mg of the title compound is obtained as a colorlessoil.

IR (film): 2923, 2851, 1739, 1655, 1370, 1240, 990 cm⁻¹.

EXAMPLE 49(+)-(5RS)-5-Hydroxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Methyl Ester Diastereomer A

An ethereal diazomethane solution is instilled until permanent yellowcoloring in a solution of 80 mg of the acid, produced according toexample 32, in 8 ml of methylene chloride at 0° C. and stirred for 15minutes at 0° C. Then, it is concentrated by evaporation in a vacuum,and the residue is chromatographed on silica gel. With hexane/ethylacetate (1+9), 70 mg of the title compound is obtained as a colorlessoil.

IR (film): 3620, 2922, 2853, 1738, 1655, 1435, 990 cm⁻¹.

EXAMPLE 50(+)-(5RS)-5-Acetoxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid Methyl Ester Diastereomer A

An ethereal diazomethane solution is instilled until permanent yellowcoloring in a solution of 48 mg of the acid, produced according toexample 33, in 5 ml of methylene chloride at 0° C. and stirred for 15minutes at 0° c. Then, it is concentrated by evaporation in a vacuum,and the residue is chromatographed on silica gel. With hexane/ethylacetate (1+1), 38 mg of the title compound is obtained as a colorlessoil.

IR (film): 3400, 2923, 2858, 1740, 1655, 1370, 1240, 990 cm⁻¹.

EXAMPLE 51(+)-(5RS)-5-Acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Methyl Ester Diastereomer A

Analogously to example 48, 51 mg of the title compound is obtained as acolorless oil from 67 mg of the acid produced according to example 42.

IR (film): 2924, 2852, 1740, 1655, 1371, 1240, 991 cm⁻¹.

EXAMPLE 52(+)-(5RS)-5-Hydroxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAid Methyl Ester Diastereomer A

Analogously to example 49, 22 mg of the title compound is obtained as acolorless oil from 29 mg of the acid produced according to example 43.

IR (film): 3600, 2922, 2852, 1738, 1655, 1436, 991 cm⁻¹.

EXAMPLE 53(+)-(5RS)-5-Acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Methyl Ester Diastereomer A

Analogously to example 50, 57 mg of the title compound is obtained as acolorless oil from 65 mg of the acid produced according to example 44.

IR (film): 3420, 2924, 2859, 1740, 1655, 1370, 1240, 990 cm⁻¹.

EXAMPLE 54(+)-(5RS)-5-Hydroxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid-1,5-lactone Diastereomer A

1 g of anhydrous magnesium sulfate is added in ports to a solution of 50mg of the acid, produced according to example 32, in 10 ml of toluene at24° C. over a period of 24 hours and stirred for another 24 hours at 24°C. Then it is filtered and the evaporation residue is chromatographed onsilica gel. With toluene/ethyl acetate (7+3), 28 mg of the lactone iseluted as a colorless oil.

IR (CHCl₃): 3620, 2930, 2860, 1726, 1248, 1045, 992 cm⁻¹.

EXAMPLE 55(+)-(5RS)-5-Hydroxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid-1,5-lactone Diastereomer B

Analogously to example 54, 30 mg of the title compound is obtained as acolorless oil from 60 mg of the acid produced according to example 37.

IR (CHCl₃): 3620, 2930, 2860, 1725, 1248, 1045, 992 cm⁻¹.

EXAMPLE 56(+)-(5RS)-5-Hydroxy-5-[trans-(2RS)-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid-1,5-lactone Diastereomer A

Analogously to example 54, 40 mg of the title compound is obtained as acolorless oil from 100 mg of the acid produced according to example 43.

IR (CHCl₃): 3600, 2930, 2860, 1726, 1248, 1046, 993 cm⁻¹.

EXAMPLE 57(+)-(5RS)-5-Hydroxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid-1,5-lactone Diastereomer B

Analogously to example 54, 23 mg of the title compound is obtained as acolorless oil from 40 mg of the acid produced according to example 46.

IR (CHCl₃): 3620, 2930, 2860, 1725, 1248, 1046, 993 cm⁻¹.

EXAMPLE 58(+)-(5RS)-5-Hydroxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicAcid-tris-(hydroxymethyl)-aminomethane Salt

A solution of 29 mg of tris-(hydroxymethyl)-aminomethane in 0.04 ml ofwater is added to a solution of 80 mg of the carboxylic acid, producedaccording to example 23, in 13 ml of acetonitrile at 70° C. It isallowed to cool with stirring, decanted after 16 hours from the solventand the residue is dried in a vacuum. 25 mg of the title compound isisolated as a waxy mass.

EXAMPLE 59(±)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-trideca-1,3-dien-7-inyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Nonpolar and Polar Diastereomer

A solution of 2.22 g of 4-chloro-1-(tert-butyldimethylsilyloxy)-butanein 2 ml of tetrahydrofuran and 0.06 ml of dibromoethane is instilled in480 mg of magnesium at 25° C. under argon, hated for 10 minutes to 60°C., stirred for 30 minutes at 25° C. and diluted with 6.2 ml oftetrahydrofuran.

4 ml of the above-produced Grignard solution is added to 922 mg ofcis-(1RS)-1-formyl-(2RS)-[(1E,3E)-(5RS)-5-tert-butyldiphenylsilyloxy-trideca-1,3-dien-7-inyl]-cyclohexanedissolved in 5 ml of tetrahydrofuran at -70° C. under argon and stirredfor 1 hour at -70° C. The reaction mixture is added to the saturatedammonium chloride solution, extracted several times with ether, theorganic phase is washed with brine, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue thus obtained isdissolved in 4 ml of pyridine, 1 ml of acetic anhydride under argon isadded and stirred for 24 hours at 24° C. Then, it is concentrated byevaporation with the addition of toluene in a vacuum. The residue ischromatographed on silica gel with hexane/0-50% of methylene chloride.487 mg of (±)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-tert-butyldiphenylsilyloxy-trideca-1,3-dien-7inyl)-(1RS)-cyclohex-1-yl]-pentan-1-ol-tert-butyldimethylsilyletheris obtained as a colorless oil.

IR: 2935, 2860, 1730, 1255, 1122, 992, 843, 705 cm⁻¹.

For selective cleavage of protecting groups, 400 mg of theabove-produced acetate in 5 ml of ethanol is stirred with 400 mg ofpyridinium-p-toluene-sulfonate for 1 hour at 60° C. under argon. Aftercooling off to 24° C., it is diluted with ether, washed twice withwater, dried on sodium sulfate and concentrated by evaporation in avacuum. The residue is chromatographed on silica gel with hexane/0-40%ethyl acetate. 227 mg of(±)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-tert-butyldiphenylsilyloxy-trideca-1,3-dien-7-inyl)-(1RS)-cyclohex-1-yl]-pentan-1-olis thus obtained as a colorless oil.

IR: 3680, 3440, 2935, 2860, 1730, 1255, 1122, 990, 705 cm⁻¹.

220 mg of the above-produced alcohol in 22 ml of methylene chloride ismixed at 0° C. under argon with 1.76 g of Collins reagent (chromicacid-pyridine complex) and stirred for 30 minutes at 0° C. It is dilutedwith hexane/ether (1+1), filtered off on Celite, subsequently washedwith hexane/ether (1+1) and concentrated by evaporation in a vacuum.

1.0 ml of Jones reagent (J. Chem. Soc. 1953, 2555) is instilled in asolution of 237 mg of the above-produced aldehyde in 10 ml of acetonewith stirring at -30° C. and stirred for 30 minutes at -20° C. underargon. Then, 0.3 ml of isopropanol is added, stirred for 10 minutes at-20° C., diluted with ether, washed neutral with brine/water (1+1),dried on sodium sulfate and concentrated by evaporation in a vacuum. Theresidue is chromatographed on silica gel with hexane/ethyl acetate(7+3). 171 mg of(±)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-tert-butyldiphenylsilyloxy-trideca-1,3-dien-7-inyl)-(1RS)-cyclohex-1-yl]-pentanoicacid is thus obtained as a colorless oil.

IR: 3520, 3200, 2935, 2860, 1725, 1255, 1120, 990, 703 cm⁻¹.

20 mg of the above-produced acid dissolved in 1 ml of tetrahydrofuran ismixed with 100 mg of tetrabutylammonium fluoride and stirred over 16hours at 24° C. under argon. Then, it is diluted with ether, washed withbrine, dried on sodium sulfate and concentrated by evaporation in avacuum. The residue is chromatographed on silica gel with hexane/30-60%of ethyl acetate. In this way, first 4.7 mg of the nonpolar diastereomerand then 5.5 mg of the polar diastereomer of the title compound areobtained as colorless oils.

IR (nonpolar diastereomer): 3590, 3410, 2930, 2860, 1725, 1250, 1120,991 cm⁻¹.

IR (polar diastereomer): 3600, 3400, 2928, 2859, 1730, 1250, 1122, 990cm⁻¹.

The initial material for the above-named title compound is produced asfollows:

a)1-[cis-(2RS)-2-(tert-Butyldimethylsilyloxymethyl)-(1RS)-cyclohex-1-yl]-(1E,3E)-(5RS)-octa-1,3-dien-7-in-5-ol

Several crystals of iodine and 12.5 mg of mercury(II) chloride are addedto 2.05 g of magnesium in 25 ml of ether. Altogether, 7.5 ml ofpropargyl bromide is instilled in the pure bromide at 24° C. until theGrignard reaction is started. Then, the residual bromide dissolved in 25ml of ether is slowly instilled at 0° C. and subsequently stirred afterthe complete addition for 1 more hour at 24° C.

63 mg of mercury(II) chloride is added to a solution of 8.1 g of5-[cis-1-(tert-butyldimethylsilyloxymethyl)-cyclohex-2-yl]-(2E,4E)-pentadien-1-al(produced according to example 12b) in 125 ml of ether and 40 ml of theabove-produced Grignard solution is instilled slowly at -70° C. underargon. Then, it is allowed to heat to 0° C. and is stirred at thistemperature for another 30 minutes. The reaction mixture is then addedto saturated ammonium chloride solution and extracted several times withether. The organic phase is washed with brine, dried on sodium sulfateand concentrated by evaporation in a vacuum. The residue ischromatographed on silica gel with hexane/0-40% of ethyl acetate. 7.48 gof the title compound is thus obtained as a colorless oil.

IR: 3390, 3315, 2930, 2860, 2120, 990, 838 cm⁻¹.

b)1-[cis-(2RS)-2-(tert-Butyldimethylsilyloxymethyl)-(1RS)-cyclohex-1-yl]-(1E,3E)-(5RS)-octa-1,3-dien-7-in-5-ol-tert-butyldiphenylsilylether

7.48 g of the above-produced alcohol dissolved in 130 ml ofdimethylformamide is mixed with 4.64 g of imidazole. 7.97 g oftert-butyl-diphenylsilyl chloride is added to this solution at 0° underargon and stirred for 16 hours at 24° C. Then, the reaction mixture isadded to water, extracted several times with hexane/ether (1+1), driedon sodium sulfate and concentrated by evaporation in a vacuum. Theresidue is chromatographed on silica gel with hexane/0-30% of ether.11.7 g of the title compound is thus obtained as a colorless oil.

IR: 3320, 2925, 2862, 2125, 1120, 992, 840, 705 cm⁻¹.

c)1-[cis-(2RS)-2-(tert-Butyldimethylsilyloxymethyl)-(1RS)-cyclohex-1-yl]-(1E,3E)-(5RS)-trideca-1,3-dien-7-in-5-ol-tert-butyldiphenylsilylether

11.7 g of the above-produced silyl ether in 100 ml of tetrahydrofuran ismixed at -70° C. under argon with 19 ml of a 1.6 molar n-butyllithiumsolution in hexane. It is allowed to heat to -10° C. and is stirred atthis temperature for 30 minutes. Then, 10 ml of a n-pentyl bromide, 16ml of hexamethylphosphoric acid triamide and 400 mg of sodium iodide areadded in succession and stirred for 6 hours at 24° C. The reactionmixture is added to water, extracted several times with ether, dried onsodium sulfate and concentrated by evaporation in a vacuum. The residueis chromatographed on silica gel with hexane/methylene chloride (8+2).7.6 g of the title compound is thus obtained as a colorless oil.

IR: 2928, 2860, 1122, 990, 838, 700 cm⁻¹.

d)cis-(1RS)-1-Hydroxymethyl-(2RS)-[(1E,3E)-(5RS)-5-tert-butyldiphenylsilyloxy-trideca-1,3-dien-7-in]-cyclohexane

100 ml of a mixture of acetic acid/water/THF (65:35:10) is added to 7.6g of the above-produced silyl ether dissolved in 100 ml oftetrahydrofuran and stirred for 10 hours to 50° C. It is concentrated byevaporation in a vacuum with the addition of toluene. The residue ischromatographed on silica gel with hexane/0-40% of ethyl acetate. 5.7 gof the title compound is thus obtained as a colorless oil.

IR: 3580, 3350, 3315, 2930, 2860, 1122, 990, 702 cm⁻¹.

e)cis-(1RS)-1-Formyl-(2RS)-[(1E,3E)-(5RS)-5-tert-butyldiphenylsilyloxy-trideca-1,3-dien-7-in]-cyclohexane

1.0 g of the above-produced alcohol in 80 ml of methylene chloride ismixed at 0° C. under argon with 6 g of Collins reagent (chromicacid-pyridine complex) and stirred for 30 minutes at 0° C. Then, it isfiltered off on Celite, subsequently washed with ether and concentratedby evaporation in a vacuum. The aldehyde thus obtained is used withoutfurther purification.

EXAMPLE 60

90 mg of(±)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-tert-butyldiphenylsilyloxy-trideca-1,3-dien-7-inyl)-(1RS)-cyclohex-1-yl]-pentanoic acid (produced in example 59) is stirred together with1.8 ml of ethanolic potassium hydroxide solution (5 g of potassiumhydroxide in 62.5 ml of water and 187.5 ml of ethanol) for 4 days at 24°C. Then, it is acidified with 10% sulfuric acid to pH 5, extractedseveral times with ethyl acetate, the organic phase is washed withbrine, dried on sodium sulfate and concentrated by evaporation in avacuum. The residue is chromatographed on silica gel with hexane/10-70%of ethyl acetate. 32 mg of(±)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-trideca-1,3-dien-7-inyl)-(1RS)-cyclohex-1-yl]-pentanoicacid is obtained.

IR: 3600, 3420, 2928, 2860, 1725, 1250, 1122, 990, 705 cm⁻¹.

32 mg of the above-produced alcohol dissolved in 1.5 ml oftetrahydrofuran is mixed at 24° C. under argon with 180 mg oftetrabutylammonium fluoride and stirred for 16 hours at thistemperature. Then, it is diluted with ether, the organic phase is washedwith brine, dried on sodium sulfate and concentrated by evaporation in avacuum. The residue is chromatographed on silica gel with hexane/30-70%of ethyl acetate. 6.5 mg of the title compound is obtained as acolorless oil.

IR: 3600, 3410, 2930, 2862, 1728, 1250, 1120, 990 cm⁻¹.

EXAMPLE 61(±)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E,7Z)-(5RS)-5-hydroxy-1,3,7-tridecatrienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomers A and B

A solution of 4.44 g of 4-chloro-1-(tert-butyldimethylsilyloxy)-butanein 4 ml of tetrahydrofuran and 0.06 ml of dibromomethane is instilled in960 mg of magnesium at 25° C. under argon, heated for 10 minutes to 60°C., stirred for 30 minutes at 25° C. and diluted with 12.4 ml oftetrahydrofuran. 9 ml of the above-produced Grignard solution is addedto 1.95 g ofcis-(1RS)-1-formyl-(2RS)-[(1E,3E,7Z)-(5RS)-5-tert-butyldiphenylsilyloxy-1,3,7-tridecatrienyl]-cyclohexanedissolved in 10 ml of tetrahydrofuran at -70° C. under argon and stirredfor 1 hour at -70° C. The reaction mixture is added to saturatedammonium chloride solution, extracted several times with ether, theorganic phase is washed with brine, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue thus obtained isdissolved in 8 ml of pyridine, 2 ml of acetic anhydride under argon isadded and stirred for 20 hours at 24° C. Then, it is concentrated byevaporation in a vacuum with the addition of toluene. The residue ischromatographed on silica gel with hexane/ether (98+2). 602 mg of anonpolar diastereomer and 621 mg of a polar diastereomer are obtained ascolorless oils from(±)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E,7Z)-(5RS)-5-tert-butyldiphenylsilyloxy-1,3,7-tridecatrienyl)-(1RS)-cyclohex-1-yl]-pentan-1-ol-tert-butyldimethylsilylether.

IR (nonpolar diastereomer): 2928, 2858, 1738, 1245, 988, 837, 703 cm⁻¹.

IR (polar diastereomer): 2928, 2857, 1738, 1243, 990, 835, 702 cm⁻¹.

2.4 ml of an HF-pyridine solution (1 ml of HF-pyridine complex+3 ml ofpyrinde+3 ml of tetrahydrofuran) is added to a solution of 240 mg of theabove-produced nonpolar acetate in 12 ml of methanol at 24° C. underargon and stirred for 6 hours at 24° c. It is diluted with ether, theorganic phase is washed with saturated sodium bicarbonate solution, withbrine, dried on sodium sulfate, filtered and concentrated by evaporationin a vacuum. The residue is chromatographed on silica gel withhexane/0-50% of ethyl acetate. 97 mg of(±)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E,7Z)-(5RS)-5-tert-butyldiphenylsilyloxy-1,3,7-tridecatrienyl)-(1RS)-cyclohex-1-yl]-pentan-1-ol(diastereomer A) is obtained as a colorless oil.

IR (diastereomer A): 3450, 2930, 2860, 1735, 1242, 988, 702 cm⁻¹.

Analogously to the above-described method, 169 mg of diastereomer B isobtained from 621 mg of the above--produced polar acetate.

IR (diastereomer B); 3440, 2929, 2858, 1738, 1242, 990, 702 cm⁻¹.

97 mg of the above-produced alcohol (diastereomer A) in 5 ml ofmethylene chloride is mixed at 0° C. under argon with 400 mg of Collinsreagent (chromic acid-pyridine complex) and stirred for 30 minutes at 0°C. It is diluted with hexane/ether (1+1), filtered off on Celite,subsequently washed with hexane/ether (1+1) and concentrated byevaporation in a vacuum. The residue thus obtained is dissolved in 4 mlof acetone, 94 ml of Jones reagent (J. Chem. Soc. 1953, 2555) isinstilled with stirring at -20° C. and stirred for 25 minutes at -20° C.under argon. Then, 0.1 ml of isopropanol is added, stirred for 10minutes at -20° C., diluted with ether, washed neutral with brine/water(1+1), dried on sodium sulfate and concentrated by evaporation in avacuum. The residue is chromatographed on silica gel with hexane/0-30%of ethyl acetate. 65 mg of(±)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E,7Z)-(5RS)-5-tert-butyldiphenylsilyloxy-1,3,7-tridecatrienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid (diastereomer A) is obtained as a colorless oil.

IR (diastereomer A): 3440, 3200, 2929, 2858, 1735, 1710, 1240, 990, 702cm⁻¹.

Analogously to the above-described methodology, 162 mg of acid(diastereomer B) is obtained as a colorless oil from 261 mg of theabove-produced alcohol (diastereomer A).

IR (diastereomer B): 3450, 3200, 2930, 2858, 1738, 1708, 1240, 988, 702cm⁻¹.

65 mg of the above-produced acid (diastereomer A) dissolved in 2.7 ml oftetrahydrofuran is mixed with 366 mg of tetrabutylammonium fluoride andstirred for 16 hours at 24° C. under argon. Then, it is diluted withether, washed with brine, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue is chromatographed on silica gelwith hexane/50-70% of ethyl acetate. 24 mg of the title compound(diastereomer A) is obtained as a colorless oil.

IR (diastereomer A): 3450, 3200, 2930, 2858, 1735, 1710, 1240, 988, 702cm⁻¹.

Analogously to the above-described methodology, 64 mg of the titlecompound (diastereomer B) is obtained as a colorless oil from 160 mg ofthe above-produced acid (diastereomer B).

IR (diastereomer B): 3440, 2928, 2857, 1710, 1242, 990 cm⁻¹.

The initial material for the above-named title compound is produced asfollows:

a)cis-(1RS)-1-Hydroxymethyl-(2RS)-[(1E,3E,7Z)-(5RS)-5-tert-butyldiphenylsilyloxy-1,3,7-tridecatrienyl]-cyclohexane

For hydrogenation, 6.2 g ofcis-(1RS)-1-hydroxymethyl-(2RS)-[(1E,3)-(5RS)-5-tert-butyldiphenylsilyloxy-trideca-1,3-dien-7-in]-cyclohexanein 2.5 l of hexane/ethyl acetate (1+1) is stirred with 6.2 g of Lindlarcatalyst for 3 hours at 24° C. in a hydrogen atmosphere. Then, it isflushed with nitrogen, filtered and concentrated by evaporation in avacuum. The residue is chromatographed on silica gel withhexane/tert-butyl methyl ether (9+1). 3.43 g of the title compound isobtained as a colorless oil.

IR: 3590, 3340, 2925, 2855, 988, 698 cm⁻¹.

b)cis-(1RS)-1-Formyl-(2RS)[(1E,3E,7Z)-(5RS)-5-tert-butyldiphenylsilyloxy-1,3,7-tridecatrienyl]-cyclohexane

Analogously to example 59e, 1.9 g of the title compound is obtained as acolorless oil from 2.0 g of the above-produced alcohol.

IR: 2930, 2858, 2720, 1718, 990, 700 cm⁻¹.

EXAMPLE 62(±)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E,7Z)-(5RS)-5-hydroxy-1,3,7-tridecatrienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer A

20 mg of(±)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E,7Z)-(5RS)-5-hydroxy-1,3,7-tridecatrienyl)-(1RS)-cyclohex-1yl]-pentanoicacid (diastereomer A, produced in example 61) dissolved in 0.6 ml ofmethanol is mixed with 0.6 ml of 0.5N lithium hydroxide solution andstirred for 24 hours at 50° C. under argon. Then, it is diluted with 1ml of water and acidified at 0° C .with a 1N sulfuric acid to pH 5. Itis extracted several times with water, the organic phase is washed withbrine, dried on sodium sulfate and concentrated by evaporation in avacuum. The residue is chromatographed on silica gel with hexane/50-90%of ethyl acetate. 11.2 mg of the title compound is obtained as acolorless oil.

IR: 3445, 2932, 2860, 1708, 1240, 990 cm⁻¹.

EXAMPLE 63(±)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E,7Z)-(5RS)-5-hydroxy-1,3,7-tridecatrienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid (Diastereomer B)

Analogously to example 62, 19 mg of the title compound is obtained as acolorless oil from 48 mg of the acid (diastereomer B) produced accordingto example 61.

IR: 3440, 2930, 2858, 1710, 1240, 990 cm⁻¹.

EXAMPLE 64(±)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentan-1-olDiastereomer A

A solution of 2.2 g of 4-chloro-1-(tert-butyldimethylsilyloxy)-butane in2 ml of tetrahydrofuran and 0.06 ml of dibromoethane is instilled in 480mg of magnesium at 25° C. under argon, heated for 10 minutes to 60° C.,stirred for 30 minutes at 25° C. and diluted with 6.2 ml oftetrahydrofuran.

3 ml of the above-produced Grignard solution is added to 670 mg ofcis-(1RS)-1-formyl-(2RS)-[(1E,3E)-(5RS)-5-acetoxy-6-(2-pentylphenyl)-1,3-hexadienyl]-cyclohexane(diastereomer A) in 5 ml of tetrahydrofuran at -70° C. under argon andstirred for 1 hour at -70° C. The reaction mixture is added to saturatedammonium chloride solution, extracted several times with ether, theorganic phase is washed with brine, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue thus obtained isdissolved in 8 ml of pyridine, 2 ml of acetic anhydride is added underargon and stirred for 24 hours at 24° C. Then, it is concentrated byevaporation in a vacuum with the addition of toluene. The residue ischromatographed on silica gel with hexane/0-10% of ethyl acetate. 304 mgof(±)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentan-1-ol-tert-butyldimethylsilylether(diastereomer A) is obtained.

IR: 2940, 2870, 1728, 1610, 1255 972, 842 cm⁻¹.

For cleavage of protecting groups, 290 mg of the above-produced acetatedissolved in 29 ml of tetrahydrofuran is mixed with 438 mg oftetrabutylammonium fluoride and stirred for 4 hours at 24° C. underargon. Then, it is diluted with ether, the organic phase is washed twicewith water, dried on magnesium sulfate and concentrated by evaporationin a vacuum. The residue is chromatographed on silica gel withhexane/0-70% of ether. 188 mg of the title compound is obtained as acolorless oil.

IR: 3700, 3640, 3500, 2940, 2870, 1730, 1610, 1250, 972 cm⁻¹.

The initial material for the above-named title compound is produced asfollows:

a) 2-pentylbenzyl alcohol

245 ml of a 1.6 molar butyllithium solution in hexane is instilled in asolution of 20.0 g of 2-methylbenzyl alcohol in 185 ml of ether underargon, so that the temperature does not exceed 10° C. Then, it isrefluxed for 5 hours, allowed to cool off to 24° C., 22.4 g of1-bromobutane is instilled and it is stirred for 16 hours at 24° C. Thereaction mixture is added to 100 ml of water and extracted three timeswith 100 ml of ether each. The organic phase is washed with brine, driedon sodium sulfate and concentrated by evaporation in a vacuum. Theresidue is chromatographed on silica gel with hexane/0-30% of ethylacetate. 20.1 g o the title compound is obtained as a colorless oil.

IR: 3540, 3320, 2930, 2860, 1605, 750 cm⁻¹.

b) 2-pentylbenzyl bromide

3.2 ml of pyridine is added to a solution of 21 g of the above-producedalcohol in 23.8 ml of ether and instilled at -10° C. under argon in 5.1ml of phosphorus tribromide. It is refluxed for 3 hours and aftercooling off to 24° C., the reaction mixture is carefully added to 40 mlof water. It is extracted three times with 150 ml of ether each, theorganic phase is washed with brine, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue is chromatographedon silica gel with hexane/0-6% of ether. 19.5 g of the title compound isobtained as a colorless oil.

IR: 2958, 2930, 2860, 1608, 760 cm⁻¹.

c)(5RS)-5-Acetoxy-1-[cis-(2RS)-2-tert-butyldimethylsilyloxymethyl)-(1RS)-cyclohex-1-yl]-6-(2-pentylphenyl)-1,3-hexadiene

Analogously to example 1c, 4.1 g of the title compound is obtained as acolorless oil from 5.7 g of the aldehyde produced according to example12b.

IR: 2930, 2858, 1735, 1605, 1240, 990, 845, 750 cm⁻¹.

d)cis-(1RS)-1-Formyl-(2RS)-[(1E,3E)-(5RS)-5-acetoxy-6-(2-pentylphenyl)-1,3-hexadienyl)-cyclohexanediastereomer A and diastereomer B

4.68 g of tetrabutylammonium fluoride is added to a solution of 3.8 g ofthe above-produced acetate in 90 ml of tetrahydrofuran at 0° C. underargon and stirred first for 30 minutes at 0° C., then for 4.5 hours at24° C. It is diluted with ether, the organic phase is washed twice withbrine/water (1+1), dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue is chromatographed on silica gelwith hexane/0-30% of ethyl acetate. In this way, first 690 mg of thenonpolar diastereomer and then 1.05 g of the polar diastereomercis-(1RS)-1-hydroxymethyl-(2RS)-[(1E,3E)-(5RS)-5-acetoxy-6-(2-pentylphenyl)-1,3-hexadienyl)-cyclohexaneare obtained as colorless oils.

IR (nonpolar diastereomer): 3440, 2925, 2857, 1738, 1605, 1235, 990, 750cm⁻¹.

IR (polar diastereomer): 3450, 2925, 2855, 1738, 1605, 1235, 990, 750cm⁻¹.

685 mg of the above-produced alcohol (nonpolar diastereomer) dissolvedin 17 ml of methylene chloride is mixed at 0° C. under argon with 3.5 gof Collins reagent and stirred for 20 minutes at 0° C. It is dilutedwith hexane/ether (2+1), filtered off on Celite, subsequently washedwith hexane/ether (2+1) and concentrated by evaporation in a vacuum. Thealdehyde thus obtained (diastereomer A) is used without furtherpurification.

Analogously to the above-described method, the aldehyde (diastereomer B)is obtained from 1.05 g of the above-produced alcohol (polardiastereomer).

EXAMPLE 65(±)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentan-1-ol(diastereomer B)

Analogously to example 64, 252 mg of the title compound is obtained as acolorless oil from 980 mg of the aldehyde (diastereomer B) producedaccording to example 64d.

IR: 3700, 3620, 3480, 2938, 2870, 1732, 1605, 1250, 992 cm⁻¹.

EXAMPLE 66(±)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer A1 and A2 diastereomer

185 mg of the alcohol, produced according to example 64, in 20 ml ofmethylene chloride is mixed at 0° C. under argon with 1.1 g of Collinsreagent (chromic acid-pyridine complex) and stirred for 30 minutes at 0°C. It is diluted with hexane/ether (1+1), filtered off on Celite,subsequently washed with hexane/ether (1+1) and concentrated byevaporation in a vacuum. The residue is dissolved in 15 ml of acetone,0.35 ml of Jones reagent (J. Chem. Soc. 1953, 2555) is instilled at -30°C. with stirring and stirred for 20 minutes at -20° C. Then, 0.5 ml ofisopropanol is added, stirred for 10 minutes at -20° C., diluted withether, washed neutral with brine/water (1+1), dried on sodium sulfateand concentrated by evaporation in a vacuum. The residue ischromatographed on silica gel with hexane/0-60% of ethyl acetate. First75 mg of nonpolar diastereomer (diastereomer A1) and then 50 mg of polardiastereomer (diastereomer A2) are obtained as colorless oils.

IR (diastereomer A1): 3520, 3180, 2937, 2860, 1730, 1605, 1250, 990cm⁻¹.

IR (diastereomer A2): 3520, 3100, 2937, 2860, 1730, 1605, 1248, 992cm⁻¹.

EXAMPLE 67(±)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer B1 and diastereomer B2

Analogously to example 66, 95 mg of nonpolar diastereomer (diastereomerB1) and 60 mg of polar diastereomer (diastereomer B2) of the titlecompound are obtained as colorless oils from 240 mg of the alcoholproduced according to example 65.

IR (diastereomer B1): 3520, 3150, 2935, 2860, 1730, 1605, 1250, 992cm⁻¹.

IR (diastereomer B2): 3520, 3100, 2937, 2862, 1730, 1605, 1248, 992cm⁻¹.

EXAMPLE 68(±)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer A1

Analogously to example 4, 35.4 mg of the title compound is obtained as acolorless oil from 70 mg of the diacetate (diastereomer A1) producedaccording to example 66.

IR: 3680, 3600, 3410, 2930, 2860, 1725, 1605, 1255, 992 cm⁻¹.

EXAMPLE 69

(±)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer B1

Analogously to example 4, 55 mg of the title compound is obtained as acolorless oil from 90 mg of the diacetate (diastereomer B1) producedaccording to example 67.

IR: 3690, 3600, 3400 2930, 2860, 1725, 1603, 1255, 993 cm⁻¹.

EXAMPLE 70(±)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer A2

Analogously to example 4, 16.4 mg of the title compound is obtained as acolorless oil from 45 mg of the diacetate (diastereomer A2) producedaccording to example 66.

IR: 3600, 3520, 3420, 2930, 2860, 1730, 1605, 1250, 992 cm⁻¹.

EXAMPLE 71(±)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer B2

Analogously to example 4, 22.4 mg of the title compound is obtained as acolorless oil from 55 mg of the diacetate (diastereomer B2) producedaccording to example 67.

IR: 3600, 3520, 3400, 2935, 2860, 1730, 1605, 1255, 992 cm⁻¹.

EXAMPLE 72(±)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer A1

Analogously to example 62, 14.8 mg of the title compound is obtained asa colorless oil from 28 mg of the monoacetate produced according toexample 68.

IR: 3680, 3520, 2930, 2860, 1728, 1605, 1248, 992 cm⁻¹.

EXAMPLE 73(±)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer B1

Analogously to example 62, 15.2 mg of the title compound is obtained asa colorless oil from 38 mg of the monoacetate produced according toexample 69.

IR: 3680, 3510, 2935, 2860, 1725, 1605, 1250, 992 cm⁻¹.

EXAMPLE 74(±)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer A2

Analogously to example 62, 3.8 mg of the title compound is obtained as acolorless oil from 13 mg of the monoacetate produced according toexample 70.

IR: 3690, 3610, 3440, 2935, 2862, 1722, 1605, 1260, 993 cm⁻¹.

EXAMPLE 75(±)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicAcid Diastereomer B2

Analogously to example 62, 7.4 mg of the title compound is obtained as acolorless oil from 18 mg of the monoacetate produced according toexample 71.

IR: 3680, 3520, 3410, 2930, 2860, 1720, 1605, 1245, 992 cm⁻¹.

We claim:
 1. A compound of formula I, ##STR24## wherein the radicalshave the following meanings: ##STR25## R¹ is CH₂ OH; CH₃ ; CF₃ ; COOR⁵,wherein R⁵ is H, a C₁₋₁₀ -alkyl radical, a C₃₋₁₀ -cycloalkyl radical, aC₆₋₁₀ -aryl radical optionally substituted by 1-3 chlorine, bromine,phenyl, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, chloromethyl, fluoromethyl,trifluoromethyl, carboxy or hydroxy groups, a --CH₂ --CO--C₆₋₁₀ -arylradical; or a 5-6-member aromatic heterocyclic radical having at least 1heteroatom N, S or O, orR¹ is CONHR⁶ whereinR⁶ is a C₁₋₁₀ -alkanoyl or-alkanesulfonyl radical or an R⁵ radical; A is a trans,trans--CH═CH--CH═CH-- group or a tetramethylene group; B is astraight-chain or branched-chain, saturated or unsaturated C₁₋₁₀-alkylene group, optionally substituted by fluorine, or the group##STR26## wherein n is 1, 2 or 3; and D is a direction bond, oxygen,sulfur, a --C.tbd.C group or a --CH═CR⁷ group whereinR⁷ is H, C₁₋₅-alkyl, chlorine, bromine or ##STR27## or B and D together are a directbond; R² and R³ are the same or different and are H or a C₁₋₁₅ -organiccarboxylic or sulfonic acid radical; R¹ and R² together are a carbonylgroup; R⁴ is H; C₁₋₁₀ -alkyl optionally substituted by chlorine orbromine; C₃₋₁₀ -cycloalkyl; a C₆₋₁ -aryl radical optionally substitutedby 1-3 chlorine, bromine, phenyl C₁₋₄ alkyl C₁₋₄ alkoxy, chloromethyl,fluoromethyl, trifluoromethyl, carboxy or hydroxy groups; or a5-6-member aromatic heterocyclic radical having at least 1 heteroatom N,S or O; andwhen R⁵ is H, a salt thereof with a physiologicallycompatible base or a cyclodextrin clathrate thereof.
 2. A compound ofclaim 1, wherein: ##STR28## R¹ is CH₂ OH, COOR⁵ wherein R⁵ I H, a C₁₋₁₀-alkyl radical, a C₅₋₆ -cycloalkyl radical, a phenyl radical optionallysubstituted by 1-2 chlorine, bromine, phenyl, C₁₋₄ alkyl, C₁₋₄ alkoxy,chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy groups,orR¹ is CONHR⁶ whereinR⁶ is a C₁₋₁₀ -alkanoyl or -alkanesulfonyl radicalor an R⁵ radical; A is a trans, trans--CH═CH--CH═CH-- group or atetramethylene group; B is a straight-chain or branched-chain, saturatedor unsaturated C₁₋₁₀ -alkylene group optionally substituted by fluorine,or the group ##STR29## wherein n is 1, 2 or 3; and D is a direct bond,oxygen, sulfur, a --C.tbd.C group or a --CH═CR⁷ group whereinR⁷ is H,C₁₋₅ -alkyl, chlorine, bromine or ##STR30## or B and D together are adirect bond; R² and R³ are the same or different and are H or a C₁₋₁₅-organic carboxylic or sulfonic acid radical; R¹ and R² together are acarbonyl group; R⁴ is a H, C₁₋₁₀ -alkyl, C₅₋₆ -cycloalkyl, a phenylradical optionally substituted by 1-2 chlorine, bromine, phenyl, C₁₋₄-alkyl, C₁₋₄ -alkoxy, chloromethyl, fluoromethyl, trifluoromethyl,carboxy, or hydroxy groups, andwherein R⁵ is H, a salt thereof with aphysiologically compatible base or a cyclodextrin clathrate thereof. 3.A compound of claim 1, wherein: ##STR31## R¹ is CH₂ OH, COOR⁵ wherein R⁵is H, or a C₁₋₄ -alkyl radical;A is a trans, trans--CH═CH--CH═CH-- groupor a tetramethylene group; B is a straight-chain or branched-chain C₁₋₅-alkylene group; and D is a direct bond or a --C.tbd.C group or a--CH═CR⁷ group wherein R² is H or C₁₋₅ -alkyl; or ##STR32## or B and Dtogether are a direct bond; R² and R³ are the same or different and areH or a C₁₋₆ -organic carboxylic or sulfonic acid radical; R¹ and R²together are a carbonyl group; R⁴ is H or a C₁₋₁₀ -alkyl, andwhen R⁵ isH, a salt thereof with a physiologically compatible base or acyclodextrin clathrate thereof.
 4. A compound of claim 1, selected fromthegroup:(+)-(5RS)5-acetoxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-acetoxy-1,3,tridecadienyl)-(1RS)-3-cyclohexen-1yl]-pentanolnonpolar and polar diastereomers;(+)-(5RS)5-acetoxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1yl]-pentanoicacid diastereomer A;(+)-(RS)-5-hydroxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicacid diastereomer A;(+)-(5RS)-5-acetoxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicacid diastereomer A;(+)-(5RS)-5-hydroxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoldiastereomer A;(+)-(5RS)-5-acetoxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoldiastereomer A;(+)-(5RS)-5-acetoxy-5-[cis-(4RS)-6-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)3-cyclohexen-1-yl]-pentanoicacid diastereomer B;(+)-(5RS)-5-hydroxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicacid diastereomer B;(+)-(5RS)-5-acetoxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicacid; diastereomer B;(+)-(5RS)-5-hydroxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1yl]-pentanoldiastereomer B;(+)-(5RS)-5-acetoxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1yl]-pentanoldiastereomer B;(+)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3tridecadienyl)-(1RS)cyclohex-1-yl]-pentanolnonpolar and polar diastereomers; (+)-(5RS)-5-acetoxy-508cis-(2RS)-2-((1E,3E)-(5RS)5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer A;(+)-(5RS)-5-hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer A;(+)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS-cyclohex-1-yl]-pentanoicacid diastereomer A;(+)-(5RS()-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer B;(+)-(5RS()-5-hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer B;(+)-(5RS()-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer B;(+)-(5RS()-5-acetoxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohexen-1-yl]-pentanoicacid methyl ester diastereomer A;(+)-(5RS)-5-hydroxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1yl]-pentanoicacid methyl ester diastereomer A;(+)-(5RS)-5-acetoxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1yl]-pentanoicacid methyl ester diastereomer A;(+)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-0((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid methyl ester diastereomer A;(+)-()5RS)-5-hydroxy-5-[cis-(2RS)-2-((1E,3E-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid methyl ester diastereomer A;(+)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid methyl ester diastereomer A;(+)-(5RS)-5-hydroxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3cyclohex-1-yl]-pentanoicacid-1,5-lactone diastereomer A;(+)-(5RS)-5-hydroxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3cyclohex-1-yl]-pentanoicacid-1,5-lactone diastereomer B;(+)-(5RS)-5-hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid-1,5-lactone diastereomer A;(+)-(5RS)-5-hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid-1,5-lactone diastereomer B;(+)-(5RS)-5-hydroxy-5-[cis-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicacid-tris-(hydroxymethyl)-aminomethane salt;(+)-(5RS)-5-acetoxy-5-[trans(6RS)-6-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanolnonpolar and polar diastereomers;(+)-(5RS)-5-acetoxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohexen-1-yl]-pentanoicacid diastereomer A;(+)-(RS)-5-hydroxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicacid diastereomer A;(+)-(5RS)-5-acetoxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicacid diastereomer A;(+)-(5RS)-5-hydroxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoldiastereomer A;(+)-(5RS)-5-acetoxy-5-[trans-(6RS)-60((1E,3E)-(5RS)-50-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanol;diastereomer A;(+)-(5RS)-5-acetoxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicacid diastereomer B;(+)-(5RS)-5-hydroxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl)-pentanoicacid diastereomer B;(+)-(5RS)-5-acetoxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicacid diastereomer B;(+)-(5RS)-5-hydroxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoldiastereomer B;(+)-(5RS)-5-acetoxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoldiastereomer B;(+)-(5RS)-5-acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanolnonpolar and polar diastereomer;(+)-(5RS)-5-acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer A;(+)-(5RS)-5-hydroxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicaid diastereomer A;(+)-(5RS)-5-acetoxy-5-[trans-(2RS)-2-((1E,1E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer A;(+)-(5RS)-5-acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer B;(+)-(5RS)-5-hydroxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer B;(+)-(5RS)-5-acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer B;(+)-(5RS)-5-acetoxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicacid methyl ester diastereomer A;(+)-(5RS)-5-hydroxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicacid methyl ester diastereomer A;(+)-(5RS)-5-acetoxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicacid methyl ester diastereomer A;(+)-(5RS)-5-acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-3-cyclohex-1-yl]-pentanoicacid methyl ester diastereomer A;(+)-(5RS)-5-hydroxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid methyl ester diastereomer A;(+)-(5RS)-5-acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid methyl ester diastereomer A;(+)-(5RS)-5-hydroxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicacid-1,5-lactone diastereomer A;(+)-(5RS)-5-hydroxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicacid-1,5-lactone diastereomer B;(+)-(5RS)-5-hydroxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid-1,5-lactone diastereomer A;(+)-(5RS)-5-hydroxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid-1,5-lactone diastereomer B;(+)-(5RS)-5-hydroxy-5-[trans-(6RS)-6-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-3-cyclohexen-1-yl]-pentanoicacid-tris-hydroxymethyl)-aminomethane salt;(+)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-trideca-1,3-dien-7-inyl)-(1RS)-cyclohex-1yl]-pentanoicacid nonpolar and polar diastereomer;(+)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E,7Z)-(5RS)-5-hydroxy-1,3,7-tridecatrienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomers A and B;(+)-(5RS)-5-hydroxy-5-[cis-(2RS)-2-((1E,3E,7Z)-(5RS)-5-hydroxy-1,3,7-tridecatrienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer A;(+)-(5RS)-5-hydroxy-5-[cis-(2RS)-5-((1E,3E,7Z)-(5RS)-5-hydroxy-1,3,7-tridecatrienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid (diastereomer B);(+)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentan-1-oldiastereomer A;(+)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentan-1-ol(diastereomer B);(+)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer A1 and A2 diastereomer;(+)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer B1 and diastereomer B2;(+)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer A1;(+)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer B1;(+)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer A2;(+)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer B2;(+)-(5RS)-5-hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer A1;(+)-(5RS)-5-hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer B1;(+)-(5RS)-5-hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer A2; or(+)-(5RS)-5-hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)5-hydroxy-6-(2-pentylphenyl)-1,3-hexadienyl)-(1RS)-cyclohex-1-yl]-pentanoicacid diastereomer B2.
 5. A pharmaceutical preparation, comprising aneffective amount of a compound of claim 1 and a pharmaceuticallyacceptable excipient.
 6. A pharmaceutical preparation of claim 5, in aform suitable for topical administration.
 7. A pharmaceuticalpreparation of claim 6, in the form of a solution, lotion, ointment,cream or plaster.
 8. A pharmaceutical preparation of claim 6, in theform of a lotion or ointment, wherein the active ingredient is presentat a concentration of 0.0001% to 1%.
 9. A pharmaceutical preparation ofclaim 5, in a form suitable for inhalation therapy.
 10. A pharmaceuticalpreparation of claim 5, in a form suitable for oral administration. 11.A pharmaceutical preparation of claim 5, in a form suitable for rectaladministration.
 12. A pharmaceutical preparation of claim 5, furthercomprising a lipoxygenase inhibitor, a cyclooxygenase inhibitor, aprostacyclin agonist, a thromboxane antagonist, a leukotriene-D₄antagonist, a leukotriene-E₄ antagonist, a leukotriene-F₄ antagonist, aphosphodiesterase inhibitor, a calcium antagonist or a PAF antagonist.13. A method of treating an inflammatory or allergic disease, comprisingadministering to a patient an effective amount of a compound of claim 1.14. A method of treating an inflammatory or allergic skin disease,comprising administering to a patient an effective amount of a compoundof claim
 1. 15. A method of claim 13, wherein the disease is arthritis,asthma, rhinitis or inflammatory intestinal disease.
 16. A method ofclaim 14, wherein the disease is eczema, erythema, psoriasis, atopicdermatitis, pruritus or acne.
 17. A method of treating fungal disease ofthe skin, comprising administering to a patient an effective amount of acompound of claim
 1. 18. A process for the production of a compound offormula I of claim 1, comprisingreacting an aldehyde of formula II,##STR33## wherein A, B, D, and R⁴ have the above-indicated meanings, andR^(3') is a silyl protecting group, optionally after protection of freehydroxy groups with a magnesium organic compound of formula III,

    X--Mg--CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --O--R.sup.8 (III),

wherein X is chlorine, bromine or iodine and R⁸ is an easily cleavableether radical, and optionally separating isomers in any sequence,releasing protected hydroxy groups, and/or esterifying a free hydroxygroup and/or oxidizing the 1-hydroxy group to carboxylic acid, and/orhydrogenating double bonds; and/or saponifying or reducing an esterifiedcarboxyl group when R¹ is COOR⁵ ; and/or esterifying a carboxyl groupwhen R⁵ is H; and/or converting a free carboxyl group, when R⁵ is H, toan amide, wherein R¹ is CONHR⁶, or converting a carboxyl group with aphysiologically compatible base to a salt.